InteractiveFly: GeneBrief

ZNF598: Biological Overview | References

Translational control exerts immediate effect on the composition, abundance, and integrity of the proteome. Ribosome-associated quality control (RQC) handles ribosomes stalled at the elongation and termination steps of translation, with ZNF598 in mammals and Hel2 in yeast serving as key sensors of translation stalling and coordinators of downstream resolution of collided ribosomes, termination of stalled translation, and removal of faulty translation products. The physiological regulation of RQC in general and ZNF598 in particular in multicellular settings is underexplored. This study shows that ZNF598 undergoes regulatory K63-linked ubiquitination in a CNOT4-dependent manner and is upregulated upon mitochondrial stresses in mammalian cells and Drosophila. ZNF598 promotes resolution of stalled ribosomes and protects against mitochondrial stress in a ubiquitination-dependent fashion. In Drosophila models of neurodegenerative diseases and patient cells, ZNF598 overexpression aborts stalled translation of mitochondrial outer membrane-associated mRNAs, removes faulty translation products causal of disease, and improves mitochondrial and tissue health. These results shed lights on the regulation of ZNF598 and its functional role in mitochondrial and tissue homeostasis (Geng. 2024).

Cells respond to stress stimuli by reconfiguring their transcriptional, translational, and metabolic profiles. Transcriptomics and proteomics studies have revealed that transcript levels and protein abundance do not always match, emphasizing the importance of post-transcriptional control of protein output. Compared to transcriptional control, translational control of available mRNAs exerts an immediate effect on the composition, abundance, and integrity of the proteome, making it particularly important under stress conditions. Moreover, mRNA translation is intrinsically a very energy-demanding process, and its regulation is intimately linked to the bioenergetic and metabolic status, making translational control essential for cellular homeostasis. Translational control critically influences cellular proliferation, growth, and survival, and impacts diverse physiological processes, from early development to synaptic plasticity. Deregulated translational control is profoundly implicated in human diseases (Geng. 2024).

Although translation is known to be tightly controlled at the rate-limiting initiation step, the elongation and termination steps are also subject to intricate regulation. During translation elongation, ribosome slowdown and stalling can occur for various reasons. Some are functional and serve to facilitate cellular dynamics, such as co-translational protein folding, frameshifting, and subcellular protein targeting. Others are detrimental and can be triggered by damaged mRNAs, mRNA secondary structures, an insufficient supply of aminoacyl-tRNAs, or environmental stress. Ribosome slowdown and stalling can result in ribosome collision, which is sensed by the cell as a proxy for aberrant translation and triggers ribosome-associated quality control (RQC) Key factors involved in the process are the ubiquitin ligase ZNF598 (Hel2 in yeast) and the 40S subunit protein Rack1 (Asc1 in yeast), which recognize the distinct 40S-40S interface of collided ribosomes and promote ubiquitination of specific 40S proteins, and the ASC complex that disassembles the leading collided ribosome. This then triggers a series of downstream quality control events, including ribosome subunit splitting and recycling by ABCE127, CAT-tailing modification by NEMF (Tae2 or Rqc2 in yeast) of nascent peptide chains (NPCs) still attached to the 60S subunit28, release of stalled NPCs from the peptidyl-tRNA/60S complex by ANKZF1 (Vms1 in yeast), and clearance of stalled NPCs by the Ltn1 E3 ligase-mediated ubiquitination and proteasomal degradation (Geng. 2024).

Recent studies have highlighted the importance of regulatory ribosomal protein ubiquitination in the RQC process. RQC is initiated by ZNF598 through site-specific mono-ubiquitination of RPS10/eS10 and RPS20/uS10 of ribosomes stalled on aberrant mRNAs, leading to the proposal that the unique 40S-40S interface of collided ribosomes is specifically recognized by ZNF598 such that problematic translation is differentiated from normal translation. Collided ribosomes marked by ZNF598-dependent ubiquitination of RPS10 are disassembled by the conserved ASC-1 complex (ASCC) containing ASCC3 (Drosophila Obelus), an ATP-dependent helicase. In addition to RPS10 and Rps20, other 40S subunits such as Rps2 and Rps3 are also mono-ubiquitinated, with ZNF598 and RNF10 having been implicated in these events. Moreover, at least in yeast, the small ribosomal protein eS7 is ubiquitinated by the E3 ligase CNOT4. CNOT4 was originally identified as a component of the CCR4-NOT complex involved in transcription and RNA degradation, but could also act as a ribosome-associated E3 ligase that works together with another ribosome-associated E3 ligase Hel2 to control RQC-uncoupled no go decay outside the disome, and CNOT4 can modify the RQC related translation termination and ribosome-recycling factor ABCE139. However, the role of CNOT4 in handling stalled translation remains poorly understood. Regulatory ribosome ubiquitination involved in RQC is also modulated at the deubiquitination step, with several enzymes having been implicated, including USP1040, OTUD341, and USP2141 that can remove the ubiquitin added by ZNF598 (Geng. 2024).

Despite growing knowledge of the players and mechanisms involved in RQC, how the RQC process is regulated by cellular signaling pathways is less understood. RQC factors are present at sub-stoichiometric levels related to the ribosomal proteins. For example, yeast ZNF598 counterpart Hel2 was reported to be present at less than 1% of the abundance of ribosomes. This low abundance of RQC factors relative to ribosomes creates a conundrum under stress conditions when the incidence of ribosome collision escalates. For example, amino acid deprivation, which leads to depletion of aminoacylated tRNAs, and alkylation and oxidation stresses, which damage RNA, are known to increase levels of ribosome collisions. Although it has been shown that when RQC is overwhelmed under excess stress and ribosome collision, the integrated stress response and ribotoxic stress response pathways can be activated, leading to cell cycle arrest and apoptosis in cultured cells, little is known about how the RQC machinery responds to stress under physiological conditions and in intact animals (Geng. 2024).

This study examined the regulation of ZNF598 under stress in mammalian cells and in vivo in Drosophila. ZNF598 was found to undergo regulatory K63-linked ubiquitination in a CNOT4-dependent manner and is upregulated upon mitochondrial stress. Overexpression (OE) of ZNF598 protects against mitochondrial stress in cultured mammalian cells, Drosophila models of neurodegenerative disease, and patient cells by aborting stalled translation of mRNAs associated with mitochondrial outer membrane and removing faulty translation products causal of disease. These results shed new light on the function of a previously unrecognized CNOT4-ZNF598 axis in mitochondrial and tissue homeostasis (Geng. 2024).

The translational machinery is intimately linked to environmental conditions, making ribosomes excellent candidates for sensors of the cellular state and platforms for various signaling pathways that respond to cellular changes. In particular, ribosome collision frequency is considered a rheostat used by the cell to select the most appropriate response to problems encountered during translation. Under normal conditions or when stresses are manageable, cells may use translation factors such as eIF5A to handle naturally occurring stalls or the RQC pathway to resolve infrequent collisions that result from aberrant mRNAs. This typically result in resumption of translation. Under these conditions, maintaining RQC factors such as ZNF598 at sub-stoichiometry relative to ribosomes may be advantages to cells, as too much ZNF598 activity may cause abortive translation of those stalls that serve physiological purposes. The situation becomes more complicated in more severe stress conditions when ribosome collisions arise. Given the low abundance of RQC factors relative to ribosomes, it is conceivable that the RQC pathway will be overwhelmed under these conditions, necessitating global stress responses or triggering cell death. The results of this study indicate that before cells succumb to stress, there is an orchestrated RQC response that upregulates the activity and abundance of ZNF598 and other RQC factors such as CNOT4 and ANKZF1. The results of this study suggest that this upregulation occurs mostly at the translational or post-translational levels at least in the case of ZNF598. This upregulation on demand helps alleviate the substoichiometry issue of ZNF598 and is important for maintaining mitochondrial and tissue homeostasis under stress. These results resonate with the emerging concept that signaling on collided ribosomes has consequences beyond that of just ribosome rescue and mRNA quality control to encompass triggering of global stress responses, including the cGAS-STING innate immune response, and cell fate decisions. It is hypothesized that this ZNF598 regulation by upstream stress signaling pathways may mechanistically link proteostasis, mitochondrial homeostasis, and innate immune response, failures of which constitute hallmarks of neurodegenerative disease (Geng. 2024).

The results of this study show that ZNF598 protein level responds to mitochondrial stress, and that its upregulation promotes the quality control of stalled cytoplasmic ribosomes associated with mitochondrial surface and the clearance of faulty translation products causal of disease in animal models of PD and ALS. The importance of ZNF598 upregulation to mitochondrial and tissue homeostasis is consistent with previous studies implicating the crosstalk between cytosolic translation and mitochondrial function, and the particular involvement of the RQC pathway in maintaining mitochondrial homeostasis. The nature of the mitochondrial signal that leads to ZNF598 ubiquitination remains to be determined. Mitochondrial outer membrane is known to be decorated with cytosolic ribosomes engaging in co-translational import of nuclear encoded mitochondrial proteins or proteins mistargeted to mitochondria, including the C-I30 and poly(GR) proteins studied in the PD and ALS models, respectively. Mitochondrial import is known to be sensitive to mitochondrial membrane potential (MMP) and other parameters of mitochondrial function. Thus, defects in the co-translational import process may lead to translation stalling and ribosome collision under mitochondrial stress. It is also possible that mitochondrial dysfunction may lead to excessive ROS production, leading to damage of mitochondria-associated mRNA. Oxidizing agents are known to modify the nucleobases of mRNAs, resulting in adducts such as 1-methyladenosine and 8-oxoguanosine, which inhibit tRNA selection by ribosomes and cause ribosome arrest. In fission yeast, oxidative stress has been shown to cause a decrease in the levels of charged Trp-tRNA and thus ribosome stalling at Trp codons. Whether similar events may occur in metazoans remains to be tested. Other signals derived from mitochondrial stress, such as mitochondrial retrograde signals or mitochondrial unfolded protein response may also impinge on the RQC pathway. Future studies will test these possibilities (Geng. 2024).

The results show that in response to mitochondrial stress, cellular RQC activity in aborting stalled translation was increased in a ZNF598-dependent manner and that ZNF598 became polyubiquitinated in the process, apparently through ubiquitination by other E3 ligase(s). Further results reveal a previously unrecognized role of the E3 ligase CNOT4 in regulating ZNF598 polyubiquitination during the RQC process in response to mitochondrial stress. CNOT4 is known to respond to mitochondrial stress and it also promotes the ubiquitination of the ribosome recycling and RQC factor ABCE139 (Pixie in Drosophila). CNOT4 was originally identified as a conserved component in the CCR4-NOT RNA quality control complex, but its importance in co-translational RQC, including regulatory ribosomal ubiquitination, is increasingly being recognized. The result is consistent with findings in budding yeast showing that CNOT4 is involved in translational repression of problematic mRNAs causing ribosome staling, and that such activity helps maintain proteome integrity upon nutrient withdrawal. Interestingly, a recent study in yeast described a role for CNOT4 in regulating mitochondrial outer membrane associated quality control of stalled translation of a mitochondrial matrix protein. CNOT4, therefore, represents a potential link between mitochondrial stress-induced defective translation and RQC. Identification of upstream regulators of the CNOT4-ZNF598 axis will further understanding of the regulation and function of the RQC pathway under physiological and stress conditions. Given the effect of PINK1 in recruiting RQC factors, including CNOT4 to mitochondrial outer membrane during mitochondrial stress, the effect of ZNF598 OE in rescuing PINK1 mutant phenotypes, and the regulation of ZNF598 protein level by PINK1 as reported in this study, genes in the PINK1 pathways are candidate upstream regulators. In this respect, the E3 ligase Parkin is a good candidate, as Parkin is known to regulate mitochondria-associated C-I30 translation and carry out K63-linked ubiquitination of substrates. Previous studies also implicated a non-canonical Notch signaling pathway in regulating RQC. It would be interesting to test a possible role of non-canonical Notch signaling in regulating the CNOT4-ZNF598 axis. Finding upstream regulators of the CNOT4-ZNF598 axis in response to mitochondrial stress will offer new insight into the regulation of RQC and help decipher how defects in this process may contribute to the pathogenesis of neurodegenerative diseases and other disorders (Geng. 2024).

Ribosome stalling during c-myc translation presents actionable cancer cell vulnerability

Myc is a major driver of tumor initiation, progression, and maintenance. Up-regulation of Myc protein level rather than acquisition of neomorphic properties appears to underlie most Myc-driven cancers. Cellular mechanisms governing Myc expression remain incompletely defined. This study showed that ribosome-associated quality control (RQC) plays a critical role in maintaining Myc protein level. Ribosomes stall during the synthesis of the N-terminal portion of cMyc, generating aberrant cMyc species and necessitating deployment of the early RQC factor ZNF598 to handle translational stress and restore cMyc translation. ZNF598 expression is up-regulated in human glioblastoma (GBM), and its expression positively correlates with that of cMyc. ZNF598 knockdown inhibits human GBM neurosphere formation in cell culture and Myc-dependent tumor growth in vivo in Drosophila. Intriguingly, the SARS-COV-2-encoded translational regulator Nsp1 impinges on ZNF598 to restrain cMyc translation and consequently cMyc-dependent cancer growth. Remarkably, Nsp1 exhibits synthetic toxicity with the translation and RQC-related factor ATP-binding cassette subfamily E member 1, which, despite its normally positive correlation with cMyc in cancer cells, is co-opted by Nsp1 to down-regulate cMyc and inhibit tumor growth. Ribosome stalling during c-myc translation thus offers actionable cancer cell vulnerability (Khaket, 2024).

RQC is emerging as an important mechanism guarding the integrity and fidelity of the proteome. Relative to the ribosomes, the RQC factors are present at substoichiometric levels, and their deficiency under stress or aging conditions can lead to failures in the maintenance of the cellular proteome and contribute to age-related neurodegenerative diseases. Despite the importance of translational control to cancer cell growth, proliferation, and differentiation, the role of RQC in cancer biology has been underexplored.This study presents evidence that the master cell growth regulator Myc represents a key RQC substrate in NSC and CSCs. This finding offers new avenues for elucidating the in vivo function of RQC, and potential new strategies to target the “undruggable” cMyc (Khaket, 2024).

This study demonstrates that ribosomes stall during the translation of the N-terminus of cMyc, resulting in the generation of stalled S-cMyc. This conclusion is supported by the following evidence: (1) S-cMyc is labeled by Pum using a protocol that selectively labels stalled nascent peptide chains (NPCs); (2) the relative abundance of S-cMyc is directly regulated by key genes in the RQC pathway that handle stalled translation; (3)) the abundance of S-cMyc is regulated by Nsp1 that also manipulates stalled translation; (4) the abundance of S-cMyc is influenced by treatment with anisomycin under conditions that induce ribosome stalling; (5) puromycin-labeled S-cMyc is associated with collided ribosomes in sucrose gradient fractionation assays; (6) the cMyc-5P mutant with putative translation stall signal altered exhibited differential in vivo effects and responses to stall inducing conditions compared with cMyc-WT in a manner unaccounted for by differential protein stability, consistent with their differential regulation by ribosome stalling. The presence of translation stall in Myc is likely to serve a physiological role rather than simply being an idiosyncrasy of c-Myc protein. As Myc hyperactivity in proliferating cells can lead to cancer, and excessive Myc expression can lead to apoptosis, tight control of Myc protein level will be a key to NSC homeostasis. Indeed, previous studies implicated a critical role of translational or posttranslational control of Myc protein expression in NSCs. Thus, despite previous studies implicating Myc as a transcriptional target of Notch signaling, and mammalian studies showing c-Myc OE being sufficient to lead to neoplastic transformation under certain conditions, transcriptional up-regulation of dMyc is insufficient to recapitulate the effect of Notch in inducing ectopic NB formation in flies, where Myc protein level remaining low despite elevated mRNA level. This suggests that there exists tight homeostatic regulation of Myc protein level in NSCs. It is hypothesized that in proliferating stem cells or cancer cells, which feature increased protein synthesis and pose increased risk for ribosome collisions, the ribosome stalling and subsequent RQC may serve as a negative feedback loop to control Myc protein level, maintain stem cell homeostasis and prevent apoptosis (Khaket, 2024).

These results show that ribosome stalling during heightened cMyc translation and the up-regulated expression of translation factors such as ABCE1 by cMyc present vulnerabilities in cMyc-driven cancers that can be targeted by Nsp1 through the ZNF598 RQC pathway. As a novel therapeutic tool, Nsp1 acts through at least two mechanisms to perturb cMyc-driven cancer growth: inhibition of cMyc expression, and synthetic lethality with genes up-regulated by cMyc (e.g. ABCE1). While further studies are needed to better understand the mechanisms of action of Nsp1 and the normal role of Nsp1 in handling stalled ribosomes in the context of viral replication and viral-host interaction, the current data suggest that Nsp1 offers a potential therapeutic agent derived from SARS-Cov-2 that can be leveraged for treating many types of human cancers driven by cMyc. Further studies will test whether RQC of stalled cMyc translation can be exploited for effective cancer therapy (Khaket, 2024). <

ZNF598 co-translationally titrates poly(GR) protein implicated in the pathogenesis of C9ORF72-associated ALS/FTD

C9ORF72-derived dipeptide repeat proteins have emerged as the pathogenic cause of neurodegeneration in amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). However, the mechanisms underlying their expression are not fully understood. This study demonstrates that ZNF598, the rate-limiting factor for ribosome-associated quality control (RQC), co-translationally titrates the expression of C9ORF72-derived poly(GR) protein. A Drosophila genetic screen identified key RQC factors as potent modifiers of poly(GR)-induced neurodegeneration. ZNF598 overexpression in human neuroblastoma cells inhibited the nuclear accumulation of poly(GR) protein and decreased its cytotoxicity, whereas ZNF598 deletion had opposing effects. Poly(GR)-encoding sequences in the reporter RNAs caused translational stalling and generated ribosome-associated translation products, sharing molecular signatures with canonical RQC substrates. Furthermore, ZNF598 and listerin 1, the RQC E3 ubiquitin-protein ligase, promoted poly(GR) degradation via the ubiquitin-proteasome pathway. An ALS-relevant ZNF598R69C mutant displayed loss-of-function effects on poly(GR) expression, as well as on general RQC. Moreover, RQC function was impaired in C9-ALS patient-derived neurons, whereas lentiviral overexpression of ZNF598 lowered their poly(GR) expression and suppressed proapoptotic caspase-3 activation. Taken together, it is proposed that an adaptive nature of the RQC-relevant ZNF598 activity allows the co-translational surveillance to cope with the atypical expression of pathogenic poly(GR) protein, thereby acquiring a neuroprotective function in C9-ALS/FTD (Park, 2021).

Proteostasis is essential for cellular physiology and is sustained by quality control pathways in gene expression. RQC represents a co-translational mechanism that triages aberrant translation intermediates via proteasomal degradation while efficiently recycling translationally stalled ribosomes. This study demonstrates that ZNF598, a key player of this molecular surveillance machinery, participates in the co-translational control of ALS-associated poly(GR) protein and suppresses cellular pathologies in ALS patient-derived neurons. Nevertheless, the underlying mechanism has features distinct from ZNF598 activity on the poly-A translation-based RQC reporter. These differences may reflect the adaptive nature and plasticity of the RQC-relevant ZNF598 function that has evolved to co-translationally surveil a myriad of ribosomal events and translational intermediates. Indeed, emerging evidence suggests that the hierarchical operation of ribosome-associating factors triggers differential molecular procedures for co-translational control and downstream signaling pathways, depending on the quality and context of ribosomal collisions (Park, 2021).

The evidence indicates that ZNF598 and LTN1 together co-translationally titrate poly(GR) expression via the ubiquitin-dependent mechanism. Comparable effects of the NEMF-LTN1 pathway on poly(GR) protein and GFP-K(AAA)20-derived AP suggest that they serve as equivalent RQC substrates. However, genetic manipulations of the ZNF598 dosage led to puzzling effects on the two translationally stalling products and downstream translation, revealing the diversity of RQC mechanisms via the substrate-specific ZNF598 function. ZNF598 deletion promoted both expressions of poly(GR) and downstream mCherry from the N-GFP-GR100 reporter, whereas ZNF598 overexpression lowered the poly(GR) levels only. Considering that ribosomal stalling cues other translation regulators to block additional translation initiation on the given mRNA molecule, ZNF598 deletion may de-repress this feedback inhibition on the N-GFP-GR100 reporter and enhance its overall translation. It was further reasoned that the translation repressor complex might be limiting in ZNF598-overexpressing cells since the overexpression phenotypes were primarily detected on the co-translational degradation of poly(GR) protein. On the other hand, ZNF598 effects on the N-GFP-K(AAA)20 reporter likely involve an RNA-dependent mechanism, and ZNF598 overexpression may promote the reporter RNA decay (83), thereby suppressing both N-GFP-K20 and mCherry expression. LTN1 depletion also displayed some interesting phenotypes, depending on ZNF598 gene dosage and translation reporters. ZNF598 acted upstream of LTN1 on the N-GFP-K(AAA)20 reporter since ZNF598 was necessary for AP generation from poly-A translation and ZNF598 deletion blocked LTN1 effects on the AP generation and downstream mCherry expression. By contrast, poly(GR) expression was promoted by non-additive effects of ZNF598 deletion and LTN1 depletion. ZNF598 deletion failed to enhance mCherry expression downstream of the poly(GR) translation in LTN1-depleted cells, suggesting a possible role of LTN1 in translational effects of ZNF598 deletion (Park, 2021).

How does ZNF598 display substrate-specific effects in RQC function? It was reasoned that the molecular context of translational stalling will determine the mode of ZNF598 action on individual RQC substrates, explaining the phenotypic difference between N-GFP-GR100 and N-GFP-K(AAA)20 reporters. Ribosomal collisions during poly-A translation may impose the rate-limiting function of ZNF598 on ribosomal disassembly that generates AP and suppresses downstream translation. Codon-independent effects of the poly(GR)-encoding sequences on translation elongation suggest that the translation products of alternating arginine residues, but not their decoding process per se, are likely responsible for translational stalling. In fact, electrostatic interactions between the positively charged nascent chain and negatively charged ribosomal RNA should delay the extrusion of translation products from ribosomes and slow down the translational elongation by individual ribosomes. Previous studies have also shown a biochemical association of arginine-containing DPR proteins with ribosomal proteins, although it is unclear whether their interaction is the cause or effect of translational stalling. It is speculated that this translational context would make ribosomal stalling on poly(GR)-encoding mRNAs less sensitive to the ZNF598 dosage. Instead, ZNF598 may play more prominent roles in facilitating the LTN1-dependent clearance of translation intermediates or blocking additional ribosome loading onto the given mRNA for relieving a translational burden (Park, 2021).

Evidence for the involvement of co-translational quality control in neurodegeneration has recently emerged. Neurodegenerative phenotypes have been documented in Ltn1 mutant mice, and a deficiency of ltn1-dependent RQC induces proteotoxic stress in yeast. These observations are consistent with motor neuron degeneration in Nemf mutant mice and NEMF association with human neuromuscular disease. Mutations in a CNS-specific tRNA and GTPBP2, a translational GTPase that interacts with the ribosome-recycling factor PELOTA, induces ribosomal stalling on a specific codon (i.e. AGA) and leads to age-dependent neurodegeneration in micex. Mitochondrial dysfunction also promotes non-templated C-terminal extensions of translation products by CAT-tailing, and co-translational quality control factors suppress their toxic expression in Parkinson’s disease models. This study illustrates how the key RQC factor ZNF598 could act as a molecular suppressor specific to C9-ALS/FTD, among other neurodegenerative disorders (Park, 2021).

In fact, co-translational mRNA surveillance mechanisms have been implicated in C9-ALS pathogenesis, and it has been shown that C9ORF72 mRNA is a substrate of NMD. However, evidence for NMD activity in C9-ALS is conflicting. The genetic conditions of NMD deficiency and C9-ALS share an overlapping gene expression profile. Transgenic overexpression of DPR proteins in cultured cells inhibits NMD, likely via the subcellular transition of the RNA-decaying P-body to stress granule. On the other hand, C9-ALS iPSNs display high rather than low NMD activity, an effect that is likely mediated by switching eRF1-dependent function from translation termination to UPF1-dependent NMD. In either case, genetic or pharmacological activation of NMD ameliorates cytotoxicity related to C9-ALS, supporting its neuroprotective role. The relevance of the UPF1-dependent mRNA surveillance pathway, however, is not limited to this specific type of ALS since UPF1 also modulates TDP-43 and FUS toxicity associated with ALS pathogenesis (Park, 2021).

Taken together, it is proposed that the ribosome-associated E3 ligases ZNF598 and LTN1 constitute an innate molecular defense that limits the atypical translation of pathogenic poly(GR) protein implicated in C9-ALS/FTD pathogenesis. These findings broaden the known repertoire of RQC-relevant physiology while being complementary to an independent study implicating CAT-tailing-like modification of poly(GR) protein in its clearance by mitochondria-associated RQC (96). Future studies should elucidate how RQC mechanisms intimately cooperate with RNA quality control pathways and translational machinery. It will also be important to understand how the RQC pathway interacts with the progress of C9-ALS/FTD for developing therapeutic opportunities (Park, 2021).

Functions of ZNF598 orthologs in other species

Ribosomal collision is not a prerequisite for ZNF598-mediated ribosome ubiquitination and disassembly of ribosomal complexes by ASCC

Ribosomal stalling induces the ribosome-associated quality control (RQC) pathway targeting aberrant polypeptides. RQC is initiated by K63-polyubiquitination of ribosomal protein uS10 located at the mRNA entrance of stalled ribosomes by the E3 ubiquitin ligase ZNF598 (Hel2 in yeast). Ubiquitinated ribosomes are dissociated by the ASC-1 complex (ASCC) (RQC-Trigger (RQT) complex in yeast). A cryo-EM structure of the ribosome-bound RQT complex suggested the dissociation mechanism, in which the RNA helicase Slh1 subunit of RQT (ASCC3 in mammals) applies a pulling force on the mRNA, inducing destabilizing conformational changes in the 40S subunit, whereas the collided ribosome acts as a wedge, promoting subunit dissociation. Using an in vitro reconstitution approach, this study found that ribosomal collision is not a strict prerequisite for ribosomal ubiquitination by ZNF598 or for ASCC-mediated ribosome release. Following ubiquitination by ZNF598, ASCC efficiently dissociated all polysomal ribosomes in a stalled queue, monosomes assembled in RRL, in vitro reconstituted 80S elongation complexes in pre- and post-translocated states, and 48S initiation complexes, as long as such complexes contained ≥ 30-35 3'-terminal mRNA nt. downstream from the P site and sufficiently long ubiquitin chains. Dissociation of polysomes and monosomes both involved ribosomal splitting, enabling Listerin-mediated ubiquitination of 60S-associated nascent chains (Miscicka, 2024).

Znf598-mediated Rps10/eS10 ubiquitination contributes to the ribosome ubiquitination dynamics during zebrafish development

The ribosome is a translational apparatus that comprises about 80 ribosomal proteins and four rRNAs. Recent studies reported that ribosome ubiquitination is crucial for translational regulation and ribosome-associated quality control (RQC). However, little is known about the dynamics of ribosome ubiquitination under complex biological processes of multicellular organisms. To explore ribosome ubiquitination during animal development, a zebrafish strain was generated that expresses a FLAG-tagged ribosomal protein Rpl36/eL36 from its endogenous locus. Ribosome ubiquitination during zebrafish development was generated by combining affinity purification of ribosomes from rpl36-FLAG zebrafish embryos with immunoblotting analysis. The findings showed that the ubiquitination of ribosomal proteins dynamically changed as development proceeded. During zebrafish development, the ribosome was shown to be ubiquitinated by Znf598, an E3 ubiquitin ligase that activates RQC. Ribosomal protein Rps10/eS10 was found to be a key ubiquitinated protein during development. Furthermore, Rps10/eS10 ubiquitination-site mutations reduced the overall ubiquitination pattern of the ribosome. These results demonstrate the complexity and dynamics of ribosome ubiquitination during zebrafish development (Ugajin, 2023).

Remodeling of the ribosomal quality control and integrated stress response by viral ubiquitin deconjugases. Nature communications

The strategies adopted by viruses to reprogram the translation and protein quality control machinery and promote infection are poorly understood. This study reports that the viral ubiquitin deconjugase (vDUB)-encoded in the large tegument protein of Epstein-Barr virus (EBV BPLF1)-regulates the ribosomal quality control (RQC) and integrated stress responses (ISR). The vDUB participates in protein complexes that include the RQC ubiquitin ligases ZNF598 and LTN1. Upon ribosomal stalling, the vDUB counteracts the ubiquitination of the 40 S particle and inhibits the degradation of translation-stalled polypeptides by the proteasome. Impairment of the RQC correlates with the readthrough of stall-inducing mRNAs and with activation of a GCN2-dependent ISR that redirects translation towards upstream open reading frames (uORFs)- and internal ribosome entry sites (IRES)-containing transcripts. Physiological levels of active BPLF1 promote the translation of the EBV Nuclear Antigen (EBNA)1 mRNA in productively infected cells and enhance the release of progeny virus, pointing to a pivotal role of the vDUB in the translation reprogramming that enables efficient virus production (Liu, 2023).

A distinct mammalian disome collision interface harbors K63-linked polyubiquitination of uS10 to trigger hRQT-mediated subunit dissociation

Translational stalling events that result in ribosome collisions induce Ribosome-associated Quality Control (RQC) in order to degrade potentially toxic truncated nascent proteins. For RQC induction, the collided ribosomes are first marked by the Hel2/ZNF598 E3 ubiquitin ligase to recruit the RQT complex for subunit dissociation. In yeast, uS10 is polyubiquitinated by Hel2, whereas eS10 is preferentially monoubiquitinated by ZNF598 in human cells for an unknown reason. This study characterized the ubiquitination activity of ZNF598 and its importance for human RQT-mediated subunit dissociation using the endogenous XBP1u and poly(A) translation stallers. Cryo-EM analysis of a human collided disome reveals a distinct composite interface, with substantial differences to yeast collided disomes. Biochemical analysis of collided ribosomes shows that ZNF598 forms K63-linked polyubiquitin chains on uS10, which are decisive for mammalian RQC initiation. The human RQT (hRQT) complex composed only of ASCC3, ASCC2 and TRIP4 dissociates collided ribosomes dependent on the ATPase activity of ASCC3 and the ubiquitin-binding capacity of ASCC2. The hRQT-mediated subunit dissociation requires the K63-linked polyubiquitination of uS10, while monoubiquitination of eS10 or uS10 is not sufficient. Therefore, it is concluded that ZNF598 functionally marks collided mammalian ribosomes by K63-linked polyubiquitination of uS10 for the trimeric hRQT complex-mediated subunit dissociation (Narita, 2022).

Deubiquitinase OTUD1 Resolves Stalled Translation on polyA and Rare Codon Rich mRNAs

OTUD1 is a deubiquitinating enzyme involved in many cellular processes including cancer and innate, immune signaling pathways. This study performed a proximity labeling-based interactome study that identifies OTUD1 largely present in the translation and RNA metabolism protein complexes. Biochemical analysis validates OTUD1 association with ribosome subunits, elongation factors and the E3 ubiquitin ligase ZNF598 but not with the translation initiation machinery. OTUD1 catalytic activity suppresses polyA triggered ribosome stalling through inhibition of ZNF598-mediated RPS10 ubiquitination and stimulates formation of polysomes. Finally, analysis of gene expression suggests that OTUD1 regulates the stability of rare codon rich mRNAs by antagonizing ZNF598 (Snaurova, 2022).

The deubiquitylase USP9X controls ribosomal stalling

When a ribosome stalls during translation, it runs the risk of collision with a trailing ribosome. Such an encounter leads to the formation of a stable di-ribosome complex, which needs to be resolved by a dedicated machinery. The initial stalling and the subsequent resolution of di-ribosomal complexes requires activity of Makorin (see Drosophila Makorin 1) and ZNF598 ubiquitin E3 ligases, respectively, through ubiquitylation of the eS10 and uS10 subunits of the ribosome. This study has developed a specific small-molecule inhibitor of the deubiquitylase USP9X. Proteomics analysis, following inhibitor treatment of HCT116 cells, confirms previous reports linking USP9X with centrosome-associated protein stability but also reveals a loss of Makorin 2 and ZNF598. USP9X was shown to interacts with both these ubiquitin E3 ligases, regulating their abundance through the control of protein stability. In the absence of USP9X or following chemical inhibition of its catalytic activity, levels of Makorins and ZNF598 are diminished, and the ribosomal quality control pathway is impaired (Clancy, 2021).

The E3 ubiquitin ligase RNF10 modifies 40S ribosomal subunits of ribosomes compromised in translation

Reversible monoubiquitination of small subunit ribosomal proteins RPS2/uS5 and RPS3/uS3 has been noted to occur on ribosomes involved in ZNF598-dependent mRNA surveillance. Subsequent deubiquitination of RPS2 and RPS3 by USP10 is critical for recycling of stalled ribosomes in a process known as ribosome-associated quality control. This study identified and characterized the RPS2- and RPS3-specific E3 ligase Really Interesting New Gene (RING) finger protein 10 (RNF10) and its role in translation. Overexpression of RNF10 increases 40S ribosomal subunit degradation similarly to the knockout of USP10. Although a substantial fraction of RNF10-mediated RPS2 and RPS3 monoubiquitination results from ZNF598-dependent sensing of collided ribosomes, ZNF598-independent impairment of translation initiation and elongation also contributes to RPS2 and RPS3 monoubiquitination. RNF10 photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) identifies crosslinked mRNAs, tRNAs, and 18S rRNAs, indicating recruitment of RNF10 to ribosomes stalled in translation. These impeded ribosomes are tagged by ubiquitin at their 40S subunit for subsequent programmed degradation unless rescued by USP10 (Garzia, 2021).

Translation stress and collided ribosomes are co-activators of cGAS

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway senses cytosolic DNA and induces interferon-stimulated genes (ISGs) to activate the innate immune system. This study reports the unexpected discovery that cGAS also senses dysfunctional protein production. Purified ribosomes interact directly with cGAS and stimulate its DNA-dependent activity in vitro. Disruption of the ribosome-associated protein quality control (RQC) pathway, which detects and resolves ribosome collision during translation, results in cGAS-dependent ISG expression and causes re-localization of cGAS from the nucleus to the cytosol. Indeed, cGAS preferentially binds collided ribosomes in vitro, and orthogonal perturbations that result in elevated levels of collided ribosomes and RQC activation cause sub-cellular re-localization of cGAS and ribosome binding in vivo as well. Thus, translation stress potently increases DNA-dependent cGAS activation. These findings have implications for the inflammatory response to viral infection and tumorigenesis, both of which substantially reprogram cellular protein synthesis (Wan, 2021).

Ribosome collisions trigger cis-acting feedback inhibition of translation initiation

Translation of aberrant mRNAs can cause ribosomes to stall, leading to collisions with trailing ribosomes. Collided ribosomes are specifically recognised by ZNF598 to initiate protein and mRNA quality control pathways. This study found using quantitative proteomics of collided ribosomes that EDF1 is a ZNF598-independent sensor of ribosome collisions. EDF1 stabilises GIGYF2 at collisions to inhibit translation initiation in cis via 4EHP. The GIGYF2 axis acts independently of the ZNF598 axis, but each pathway's output is more pronounced without the other. It is proposed that the widely conserved and highly abundant EDF1 monitors the transcriptome for excessive ribosome density, then triggers a GIGYF2-mediated response to locally and temporarily reduce ribosome loading. Only when collisions persist is translation abandoned to initiate ZNF598-dependent quality control. This tiered response to ribosome collisions would allow cells to dynamically tune translation rates while ensuring fidelity of the resulting protein products (Juszkiewicz, 2920b).

The ASC-1 Complex Disassembles Collided Ribosomes

Translating ribosomes that slow excessively incur collisions with trailing ribosomes. Persistent collisions are detected by ZNF598, a ubiquitin ligase that ubiquitinates sites on the ribosomal 40S subunit to initiate pathways of mRNA and protein quality control. The collided ribosome complex must be disassembled to initiate downstream quality control, but the mechanistic basis of disassembly is unclear. This study reconstituted the disassembly of a collided polysome in a mammalian cell-free system. The widely conserved ASC-1 complex (ASCC) containing the ASCC3 helicase disassembles the leading ribosome in an ATP-dependent reaction. Disassembly, but not ribosome association, requires 40S ubiquitination by ZNF598, but not GTP-dependent factors, including the Pelo-Hbs1L ribosome rescue complex. Trailing ribosomes can elongate once the roadblock has been removed and only become targets if they subsequently stall and incur collisions. These findings define the specific role of ASCC during ribosome-associated quality control and identify the molecular target of its activity (Juszkiewicz, 2020b).

Attenuation of the Innate Immune Response against Viral Infection Due to ZNF598-Promoted Binding of FAT10 to RIG-I

Excessive innate immune response is harmful to the host, and aberrant activation of the cytoplasmic viral RNA sensors RIG-I and MDA5 leads to autoimmune disorders. ZNF598 is an E3 ubiquitin ligase involved in the ribosome quality control pathway. It is also involved in the suppression of interferon (IFN)-stimulated gene (ISG) expression; however, its underlying mechanism is unclear. This study shows that ZNF598 is a negative regulator of the RIG-I-mediated signaling pathway, and endogenous ZNF598 protein binds to RIG-I. ZNF598 ubiquitin ligase activity is dispensable for the suppression of RIG-I signaling. Instead, ZNF598 delivers a ubiquitin-like protein FAT10 to the RIG-I protein, resulting in the inhibition of RIG-I polyubiquitination, which is required for triggering downstream signaling to produce type I IFN. Moreover, ZNF598-mediated suppression is abrogated by FAT10 knockout. These data elucidate the mechanism by which ZNF598 inhibits RIG-I-mediated innate immune response (Wang, 2019).

GIGYF1/2-Driven Cooperation between ZNF598 and TTP in Posttranscriptional Regulation of Inflammatory Signaling

Inflammatory signaling is restricted through degradation and the translational repression of cytokine mRNAs. A key factor in this regulation is tristetraprolin (TTP), an RNA-binding protein (RBP) that recruits RNA-destabilizing factors and the translation inhibitory complex 4EHP-GIGYF1/2 to AU-rich element (ARE)-containing mRNAs. This study shows that the RBP ZNF598 contributes to the same regulatory module in a TTP-like manner. Similar to TTP, ZNF598 harbors three proline-rich motifs that bind the GYF domain of GIGYF1. RNA sequencing experiments showed that ZNF598 is required for the regulation of known TTP targets, including IL-8 and CSF2 mRNA. Furthermore, it was demonstrate that ZNF598 binds to IL-8 mRNA, but not TNF mRNA. Collectively, these findings highlight that ZNF598 functions as an RBP that buffers the level of a range of mRNAs. It is proposed that ZNF598 is a TTP-like factor that can contribute to the regulation of the inflammatory potential of cytokine-producing cells (Yolirnaere,2019).

ZNF598 Plays Distinct Roles in Interferon-Stimulated Gene Expression and Poxvirus Protein Synthesis

Post-translational modification of ribosomal subunit proteins (RPs) is emerging as an important means of regulating gene expression. Recently, regulatory ubiquitination of small RPs RPS10 and RPS20 by the ubiquitin ligase ZNF598 was found to function in ribosome sensing and stalling on internally polyadenylated mRNAs during ribosome quality control (RQC). This study reveals that ZNF598 and RPS10 negatively regulate interferon-stimulated gene (ISG) expression in primary cells, depletion of which induced ISG expression and a broad antiviral state. However, cell lines lacking interferon responses revealed that ZNF598 E3 ligase activity and ubiquitination of RPS20, but not RPS10, were specifically required for poxvirus replication and synthesis of poxvirus proteins whose encoding mRNAs contain unusual 5' poly(A) leaders. These findings reveal distinct functions for ZNF598 and its downstream RPS targets, one that negatively regulates ISG expression and infection by a range of viruses while the other is positively exploited by poxviruses (DiGiuseppe, 2018).

ZNF598 Is a Quality Control Sensor of Collided Ribosomes

Aberrantly slow translation elicits quality control pathways initiated by the ubiquitin ligase ZNF598. How ZNF598 discriminates physiologic from pathologic translation complexes and ubiquitinates stalled ribosomes selectively is unclear. This study found that the minimal unit engaged by ZNF598 is the collided di-ribosome, a molecular species that arises when a trailing ribosome encounters a slower leading ribosome. The collided di-ribosome structure reveals an extensive 40S-40S interface in which the ubiquitination targets of ZNF598 reside. The paucity of 60S interactions allows for different ribosome rotation states, explaining why ZNF598 recognition is indifferent to how the leading ribosome has stalled. The use of ribosome collisions as a proxy for stalling allows the degree of tolerable slowdown to be tuned by the initiation rate on that mRNA; hence, the threshold for triggering quality control is substrate specific. These findings illustrate how higher-order ribosome architecture can be exploited by cellular factors to monitor translation status (Juszkiewicz, 2018).

The E3 ubiquitin ligase and RNA-binding protein ZNF598 orchestrates ribosome quality control of premature polyadenylated mRNAs

Cryptic polyadenylation within coding sequences (CDS) triggers ribosome-associated quality control (RQC), followed by degradation of the aberrant mRNA and polypeptide, ribosome disassembly and recycling. Although ribosomal subunit dissociation and nascent peptide degradation are well-understood, the molecular sensors of aberrant mRNAs and their mechanism of action remain unknown. The Zinc Finger Protein 598 (ZNF598) was studied using PAR-CLIP and revealed that it cross-links to tRNAs, mRNAs and rRNAs, thereby placing the protein on translating ribosomes. Cross-linked reads originating from AAA-decoding tRNA(Lys)(UUU) were 10-fold enriched over its cellular abundance, and poly-lysine encoded by poly(AAA) induced RQC in a ZNF598-dependent manner. Encounter with translated polyA segments by ZNF598 triggered ubiquitination of several ribosomal proteins, requiring the E2 ubiquitin ligase UBE2D3 to initiate RQC. Considering that human CDS are devoid of >4 consecutive AAA codons, sensing of prematurely placed polyA tails by a specialized RNA-binding protein is a novel nucleic-acid-based surveillance mechanism of RQC (Garzia, 2017).

ZNF598 and RACK1 Regulate Mammalian Ribosome-Associated Quality Control Function by Mediating Regulatory 40S Ribosomal Ubiquitylation

Ribosomes that experience terminal stalls during translation are resolved by ribosome-associated quality control (QC) pathways that oversee mRNA and nascent chain destruction and recycle ribosomal subunits. The proximal factors that sense stalled ribosomes and initiate mammalian ribosome-associated QC events remain undefined. This study demonstrates that the ZNF598 ubiquitin ligase and the 40S ribosomal protein RACK1 help to resolve poly(A)-induced stalled ribosomes. They accomplish this by regulating distinct and overlapping regulatory 40S ribosomal ubiquitylation events. ZNF598 primarily mediates regulatory ubiquitylation of RPS10 and RPS20, whereas RACK1 regulates RPS2, RPS3, and RPS20 ubiquitylation. Gain or loss of ZNF598 function or mutations that block RPS10 or RPS20 ubiquitylation result in defective resolution of stalled ribosomes and subsequent readthrough of poly(A)-containing stall sequences. Together, these results indicate that ZNF598, RACK1, and 40S regulatory ubiquitylation plays a pivotal role in mammalian ribosome-associated QC pathways (Sundaramoorthy, 2017).

Search PubMed for articles about Drosophila ZNF598

Clancy, A., Heride, C., Pinto-Fernández, A., Elcocks, H., Kallinos, A., Kayser-Bricker, K. J., Wang, W., Smith, V., Davis, S., Fessler, S., McKinnon, C., Katz, M., Hammonds, T., Jones, N. P., O'Connell, J., Follows, B., Mischke, S., Caravella, J. A., Ioannidis, S., Dinsmore, C., Kim, S., Behrens, A., Komander, D., Kessler, B. M., Urbé, S., Clague, M. J. (2021). The deubiquitylase USP9X controls ribosomal stalling. The Journal of cell biology, 220(3) PubMed ID: 33507233

DiGiuseppe, S., Rollins, M. G., Bartom, E. T., Walsh, D. (2018). ZNF598 Plays Distinct Roles in Interferon-Stimulated Gene Expression and Poxvirus Protein Synthesis. Cell reports, 23(5):1249-1258 PubMed ID: 29719242

Garzia, A., Jafarnejad, S. M., Meyer, C., Chapat, C., Gogakos, T., Morozov, P., Amiri, M., Shapiro, M., Molina, H., Tuschl, T., Sonenberg, N. (2017). The E3 ubiquitin ligase and RNA-binding protein ZNF598 orchestrates ribosome quality control of premature polyadenylated mRNAs. Nature communications, 8:16056 PubMed ID: 28685749

Garzia, A., Meyer, C., Tuschl, T. (2021). The E3 ubiquitin ligase RNF10 modifies 40S ribosomal subunits of ribosomes compromised in translation. Cell reports, 36(5):109468 PubMed ID: 34348161

Geng, J., Li, S., Li, Y., Wu, Z., Bhurtel, S., Rimal, S., Khan, D., Ohja, R., Brandman, O., Lu, B. (2024). Stalled translation by mitochondrial stress upregulates a CNOT4-ZNF598 ribosomal quality control pathway important for tissue homeostasis. Nat Commun, 15(1):1637 PubMed ID: 38388640

Juszkiewicz, S., Chandrasekaran, V., Lin, Z., Kraatz, S., Ramakrishnan, V., Hegde, R. S. (2018). ZNF598 Is a Quality Control Sensor of Collided Ribosomes. Molecular cell, 72(3):469-481.e467 PubMed ID: 30293783

Juszkiewicz, S., Speldewinde, S. H., Wan, L., Svejstrup, J. Q., Hegde, R. S. (2020a). The ASC-1 Complex Disassembles Collided Ribosomes. Molecular cell, 79(4):603-614. PubMed ID: 32579943

Juszkiewicz, S., Slodkowicz, G., Lin, Z., Freire-Pritchett, P., Peak-Chew, S. Y., Hegde, R. S. (2020b). Ribosome collisions trigger cis-acting feedback inhibition of translation initiation. eLife, 9 PubMed ID: 32657267

Khaket, T. P., Rimal, S., Wang, X., Bhurtel, S., Wu, Y. C., Lu, B. (2024). Ribosome stalling during c-myc translation presents actionable cancer cell vulnerability. PNAS nexus, 3(8):pgae321 PubMed ID: 39161732

Liu, J., Nagy, N., Ayala-Torres, C., Aguilar-Alonso, F., Morais-Esteves, F., Xu, S., Masucci, M. G. (2023). Remodeling of the ribosomal quality control and integrated stress response by viral ubiquitin deconjugases. Nature communications, 14(1):8315 PubMed ID: 38097648

Miscicka, A., Bulakhov, A. G., Kuroha, K., Zinoviev, A., Hellen, C. U. T., Pestova, T. V. (2024). Ribosomal collision is not a prerequisite for ZNF598-mediated ribosome ubiquitination and disassembly of ribosomal complexes by ASCC. Nucleic acids research, 52(8):4627-4643 PubMed ID: 38366554

Narita, M., Denk, T., Matsuo, Y., Sugiyama, T., Kikuguchi, C., Ito, S., Sato, N., Suzuki, T., Hashimoto, S., Machová, I., Tesina, P., Beckmann, R., Inada, T. (2022). A distinct mammalian disome collision interface harbors K63-linked polyubiquitination of uS10 to trigger hRQT-mediated subunit dissociation. Nature communications, 13(1):6411 PubMed ID: 36302773

Park, J., Lee, J., Kim, J. H., Lee, J., Park, H., Lim, C. (2021). ZNF598 co-translationally titrates poly(GR) protein implicated in the pathogenesis of C9ORF72-associated ALS/FTD. Nucleic Acids Res, 49(19):11294-11311 PubMed ID: 34551427

Snaurova, R., Vdovin, A., Durech, M., Nezval, J., Zihala, D., Jelinek, T., Hajek, R., Simicek, M. (2022). Deubiquitinase OTUD1 Resolves Stalled Translation on polyA and Rare Codon Rich mRNAs. Mol Cell Biol, 42(12):e0026522 PubMed ID: 36445135

Sundaramoorthy, E., Leonard, M., Mak, R., Liao, J., Fulzele, A., Bennett, E. J. (2017). ZNF598 and RACK1 Regulate Mammalian Ribosome-Associated Quality Control Function by Mediating Regulatory 40S Ribosomal Ubiquitylation. Molecular cell, 65(4):751-760 PubMed ID: 28132843

Tollenaere, M. A. X., Tiedje, C., Rasmussen, S., Nielsen, J. C., Vind, A. C., Blasius, M., Batth, T. S., Mailand, N., Olsen, J. V., Gaestel, M., Bekker-Jensen, S. (2019). GIGYF1/2-Driven Cooperation between ZNF598 and TTP in Posttranscriptional Regulation of Inflammatory Signaling. Cell reports, 26(13):3511-3521.e3514 PubMed ID: 30917308

Ugajin, N., Imami, K., Takada, H., Ishihama, Y., Chiba, S., Mishima, Y. (2023). Znf598-mediated Rps10/eS10 ubiquitination contributes to the ribosome ubiquitination dynamics during zebrafish development. RNA (New York, NY), 29(12):1910-1927 PubMed ID: 37751929

Wan, L., Juszkiewicz, S., Blears, D., Bajpe, P. K., Han, Z., Faull, P., Mitter, R., Stewart, A., Snijders, A. P., Hegde, R. S., Svejstrup, J. Q. (2021). Translation stress and collided ribosomes are co-activators of cGAS. Molecular cell, 81(13):2808-2822.e2810 PubMed ID: 34111399

Wang, G., Kouwaki, T., Okamoto, M., Oshiumi, H. (2019). Attenuation of the Innate Immune Response against Viral Infection Due to ZNF598-Promoted Binding of FAT10 to RIG-I. Cell reports, 28(8):1961-1970.e1964 PubMed ID: 31433974

date revised: 10 September 2025

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