Traf1


DEVELOPMENTAL BIOLOGY

The expression of Traf1 during embryogenesis is highly dynamic and complex. Expression is observed in pre-blastoderm embryos indicative of a maternal complement that disappears after blastoderm formation. In these early embryos and throughout gastrulation, expression is most prominent in vitellophages. In contrast to the expression of murine TRAF4 (Masson, 1998), Traf1 transcripts are not predominant in neural tissues. However, they are detected in neural precursors -- the delaminating neuroblasts of the central, peripheral and stomatogastric nervous system of the embryo. Traf1 transcripts accumulate apically in embryonic neuroblasts already before the actual delamination process but quickly disappear thereafter and are no longer observed in ganglion mother cells or neurons. They are seen in a selection of presumptive sensory organ precursor cells in imaginal discs and a few neurons of the larval thoracic ganglion. The most consistent expression of Traf1 is observed in the mesoderm throughout development. Already before invagination, the presumptive mesoderm accumulates Traf1 mRNA. Expression can be followed throughout embryogenesis and is also detected in the adepithelial cells of wing imaginal discs, the presumptive imaginal muscle precursors. In contrast to other tissues, where Traf1 expression is rather transient, expression in the mesoderm persists throughout development except for terminally differentiated cells. In summary, Traf1 accumulates in mesodermal cells and neural precursors and is correlated with the onset of morphogenetic and cellular movements. It is largely absent from terminally differentiated cells (Preiss, 2001).

The larval brain accumulates Traf1 mRNA in the inner proliferation center of the optic lobe and in several single neuroblasts in the thoracic ganglion. In addition, the ring gland stains quite strongly. In the eye imaginal disc, Traf1 accumulation is seen behind the morphogenetic furrow in single cells or small groups of cells within the differentiating ommatidia. These cells may correspond to a subset of photoreceptor cells. In the antennal disc, mRNA staining is discernable in the center of the third and in a ring within the second segment. In the leg discs, single cells or small cell groups stain in those regions, from where proneural clusters for future mechano-sensory organs arise. In the prothoracic leg disc, the large cluster of the presumptive large chordotonal organ is most conspicuous. Wing discs stain most strongly in the adepithelial cells on the thoracic part that correspond to imaginal mesodermal precursor cells. Furthermore, staining is apparent on either side of the dorso-ventral boundary. It is stronger in the anterior compartment, where proneural clusters for mechano- and chemo-sensory organs of the wing margin arise. Also in the thoracic region, areas of presumptive proneural clusters stain (Preiss, 2001).

Effects of Mutation or Deletion

Traf1ex1 mutant failed to develop into the pupal stage. In order to understand the cause of the lethality, the internal organ structures of Traf1ex1 larvae were examined. The brain-ventral ganglia complex of the mutant larva showed no apparent defects compared to the wild-type control. However, interestingly, the mutant larva contained small-sized imaginal discs, especially the eye discs, in comparison to the wild-type discs. To examine the photosensory neuron projections in the brain hemisphere, eye-brain complexes were stained with monoclonal antibody 22C10, a well-characterized probe for sensory neurons in Drosophila. Axons from wild-type photoreceptors fan out evenly upon leaving the optic stalk and form a smooth neuronal array in the lamina. On the other hand, the photoreceptor axons from Traf1ex1 mutant form few axonal bundles and fail to defasciculate in the brain hemisphere. These findings suggest that Traf1 is indispensable for the development of imaginal eye discs and the formation of a correct photosensory neuronal array in the brain hemisphere (Cha, 2003).

Drosophila homologs of mammalian TNF/TNFR-related molecules regulate segregation of Miranda/Prospero in neuroblasts

During neuroblast (NB) divisions, cell fate determinants Prospero (Pros) and Numb, together with their adaptor proteins Miranda (Mira) and Partner of Numb, localize to the basal cell cortex at metaphase and segregate exclusively to the future ganglion mother cells (GMCs) at telophase. In inscuteable mutant NBs, these basal proteins are mislocalized during metaphase. However, during anaphase/telophase, these mutant NBs can partially correct these earlier localization defects and redistribute cell fate determinants as crescents to the region where the future GMC 'buds' off. This compensatory mechanism has been referred to as 'telophase rescue'. The Drosophila homolog of the mammalian tumor-necrosis factor (TNF) receptor-associated factor (TRAF1) and Eiger (Egr), the homolog of the mammalian TNF, are required for telophase rescue of Mira/Pros. TRAF1 localizes as an apical crescent in metaphase NBs and this apical localization requires Bazooka (Baz) and Egr. The Mira/Pros telophase rescue seen in inscuteable mutant NBs requires TRAF1. These data suggest that TRAF1 binds to Baz and acts downstream of Egr in the Mira/Pros telophase rescue pathway (Wang, 2006).

In telophase NBs, segregation of cell fate determinants, such as Pros, into future GMCs, is critical for their proper development. Telophase rescue appears to be one of the safeguard mechanisms that acts to ensure that GMCs inherit the cell fate determinants and adopt the correct cell identity when the mechanisms, which normally operate during NB divisions, fail (e.g., in insc mutant). Telophase rescue is a phenomenon for which the underlying mechanism involved remains largely unknown. The current data demonstrate that TRAF1 and Egr are two members of the Insc-independent telophase rescue pathway specific for Mira/Pros (Wang, 2006).

Although it is apically enriched in mitotic NBs and can directly interact with Baz in vitro, TRAF1 does not seem to be involved with the functions normally associated with the apical complex proteins. One distinct feature of TRAF1 differs from the other known apical proteins is its localization pattern; it is cytoplasmic in interphase and the apical crescent is prominent only at metaphase. In contrast, proteins of the apical complex are largely undetectable during interphase and form distinct apical crescents, starting from late interphase or early prophase. The protein localization difference between TRAF1 and other apical proteins suggests that TRAF1 and apical proteins are not always colocalized during mitosis. If TRAF1 is a bona fide member of the apical complex, the localization defects of other apical proteins are expected to be observed in TRAF1 mutant, as well as mislocalization of basal proteins, which was not detect. In addition, no spindle orientation or geometry defects were observed in the absence of TRAF1. Based on these observations, it is concluded that TRAF1 is not involved with the functions normally associated with the apical complex proteins (Wang, 2006).

The in vitro GST fusion protein pull-down assay suggests that TRAF1 may physically bind to Baz. This result is consistent with genetic data, indicating that TRAF1 acts downstream of baz and that its apical localization requires baz. These observations are consistent with the view that TRAF1 is recruited to the apical cortex by apical Baz in mitotic NBs. Baz, even at very low levels, can recruit TRAF1 to the apical cortex of the mitotic NBs. For example, in insc mutant NBs, TRAF1 remains apical probably owing to the low levels of Baz that remain localized to the apical cortex. This speculation is supported by Mira/Pros telophase rescue data, which clearly demonstrate that the telophase rescue seen in insc mutant NBs is severely damaged in baz mutant, suggesting that the Baz function required for Mira/Pros (and Pon/Numb) telophase rescue is intact in insc mutant NBs (Wang, 2006).

It has been shown that Pins/Gαi asymmetric cortical localization can be induced at metaphase by the combination of astral microtubules, kinesin Khc-73 and Dlg in the absence of Insc; this coincides with the observation that TRAF1 also forms tight crescent only at metaphase in both WT and insc mutant NBs. Does TRAF1 apical crescent formation also require the functions of astral microtubules, kinesin Khc-73 and Dlg? The data do not favor this hypothesis based on the following observations. (1) In TE35BC-3, a small deficiency uncovering sna family genes insc is not expressed but Pins and Gαi are asymmetrically localized, indicating that the astral microtubules, kinesin Khc-73 and Dlg pathway remain functional. TRAF1 is delocalized and is uniformly cortical in this deficiency line. (2) Similarly, in egr insc NBs, TRAF1 is cytoplasmic whereas the functions of astral microtubules, kinesin Khc-73 and Dlg are intact. (3) In egr NBs TRAF1 is cytoplasmic, whereas the apical complex is normal and astral microtubules, kinesin Khc-73 and Dlg are present. (4) TRAF1 apical localization remains unchanged in dlg mutant NBs. Based on these observations, it is concluded that TRAF1 apical localization is unlikely to share similar mechanism with Pins and Gαi and is likely to be independent of astral microtubules, kinesin Khc-73 and Dlg. TRAF1 apical localization appears to specifically require Egr and Baz (Wang, 2006).

In TRAF1 insc double-mutant embryos, the complete segregation of Mir/Pros into future GMCs occurs only in about 12% of the total population, and in the remaining NBs, only a fraction of Mira/Pros segregate into future GMCs as indicated by the Mira 'tail' extending into the future NBs at telophase. As it is difficult to address the global effect of this partial segregation of Mira/Pros on GMC specification in TRAF1 insc double mutant, focus was place on a well-defined GMC, GMC4-2a in NB4-2 lineage, to evaluate this issue. It is assumed that as long as the RP2 neuron (progeny of GMC4-2a, Even-skipped (Eve)-positive) was identified in a particular hemisegment, the GMC cell fate of GMC4-2a in that hemisegment should have been correctly specified. In insc mutants, almost all hemisegments contain RP2s, indicating that GMC4-2a has adopted the correct GMC cell fate in 99% of the total hemisegments. When TRAF1 insc double-mutant embryos were stained with anti-Eve, it was found the frequency of loss of Eve-positive RP2 neuron increased (to 8%) in late embryos, suggesting that about 8% of the GMCs in TRAF1 insc double mutant did not inherit sufficient Pros to specify the GMC fate in these embryos. The relatively low frequency (8%) of mis-specification of GMCs suggests that the threshold amount of Pros protein needed is sufficiently low such that just a partial inheritance of Pros, even when telophase rescue is compromised, is sufficient for most GMCs to be correctly specified (Wang, 2006).

Although Mira/Pros and Pon/Numb share similar basal localization patterns in insc NBs, further removal of either TRAF1 or Egr compromised telophase rescue only for Mira/Pros, but not for Pon/Numb. This difference between Mira/Pros and Pon/Numb indicates that the detailed mechanisms of basal localization and segregation of Mira/Pros differ from those of Pon/Numb, which is consistent with the observations that the dynamics of Mira/Pros and Pon/Numb localization early in mitosis are different and the basal localization for Mira/Pros and Pon/Numb requires different regions of the Insc coding sequence (Wang, 2006).

Dlg/Lgl/Scrib are required for correct basal localization of Mira/Pros and Pon/Numb in mitotic NBs. Dlg has been shown to be involved in the Mira telophase rescue. In dlg insc double-mutant NBs, not only was spindle geometry symmetric but Mira telophase rescue was also affected. It would be interesting to know if Dlg belongs to the same pathway as TRAF1 and Egr and if Dlg is also involved in Pon/Numb telophase rescue (Wang, 2006).

Two other members of the TRAF family have also been identified in Drosophila: DTRAF2 (DTRAF6) and DTRAF3. In contrast to the specific and strong expression of TRAF1 in the embryonic NBs, only low levels of ubiquitous signals similar to the control background were seen in the NBs with DTRAF2 and DTRAF3 probes. It is likely that DTRAF2 and DTRAF3 are not expressed in NBs and do not play an important role in Mira/Pros telophase rescue pathway as the Mira/Pros telophase rescue is dramatically compromised in TRAF1 insc and egr insc NBs (Wang, 2006).

In mammals, the TNF pathway works as a typical receptor-mediated signal transduction pathway. TNFR is a key player in transducing external signal to the cytoplasm. In the Drosophila compound eyes, ectopic Egr, Wgn and TRAF1 seem to work in a similar receptor-mediated signal pathway to induce apoptosis through the activation of the JNK pathway. Does the same Egr, Wgn and TRAF1 receptor-mediated signal pathway play a role in Mira/Pros telophase rescue? If it does, the coexpression of Egr, Wgn and TRAF1 might be expected to be seen in dividing NBs, along with the potential interaction between TRAF1 and the cytoplasmic domain of Wgn. Three observations argue against this hypothesis: (1) wgn is not expressed in embryonic NBs but in the mesoderm. (2) The domain analysis suggests that the Drosophila Wgn cytoplasmic domain is unique with no sequence homology to any mammalian TNFR family members and has neither a TRAF-binding domain nor a death domain, which is required for the interaction between TNFR and TRAF in mammals. (3) More informatively, Wgn knockdown by a UAS head-to-head inverted repeat construct of wgn (UAS-wgn-IR) driven by a strong maternal driver, mata-gal4 V32A, in WT embryos did not affect TRAF1 apical localization. These observations are consistent with the view that the receptor Wgn may not be involved in Mira/Pros telophase rescue or is redundant in this pathway. If this is the case, then how do TRAF1 and Egr function in Mira/Pros telophase rescue? It has been reported that TRAFs associate with numerous receptors other than the TNFR superfamily in mammals. It is speculated that Egr and TRAF1 may adopt an alternative receptor in NBs for Mira/Pros telophase rescue. However, until an anti-Wgn antibody and wgn mutant alleles are available, the possibility that Wgn is involved in Mira/Pros telophase rescue cannot be ruled out (Wang, 2006).

Drosophila muscleblind is involved in troponin T alternative splicing and apoptosis; Identification of dominant suppressors and enhancers of a muscleblind overexpression phenotype

Muscleblind-like proteins (MBNL) have been involved in a developmental switch in the use of defined cassette exons. Such transition fails in the CTG repeat expansion disease myotonic dystrophy due, in part, to sequestration of MBNL proteins by CUG repeat RNA. Four protein isoforms (MblA-D) are coded by the unique Drosophila muscleblind gene. This study used evolutionary, genetic and cell culture approaches to study muscleblind (mbl) function in flies. The evolutionary study showed that the MblC protein isoform was readily conserved from nematodes to Drosophila, which suggests that it performs the most ancestral muscleblind functions. Overexpression of MblC in the fly eye precursors leads to an externally rough eye morphology. This phenotype has been used in a genetic screen to identify five dominant suppressors and 13 dominant enhancers including Drosophila CUG-BP1 homolog arrest, exon junction complex components tsunagi and always early, and pro-apoptotic genes Traf1 and reaper. This study further investigated Muscleblind implication in apoptosis and splicing regulation. Missplicing of troponin T was found in muscleblind mutant pupae, and Muscleblind ability to regulate mouse fast skeletal muscle Troponin T (TnnT3) minigene splicing was confirmed in human HEK cells. MblC overexpression in the wing imaginal disc activated apoptosis in a spatially restricted manner. Bioinformatics analysis identified a conserved FKRP motif, weakly resembling a sumoylation target site, in the MblC-specific sequence. Site-directed mutagenesis of the motif revealed no change in activity of mutant MblC on TnnT3 minigene splicing or aberrant binding to CUG repeat RNA, but altered the ability of the protein to form perinuclear aggregates and enhanced cell death-inducing activity of MblC overexpression. Taken together these genetic approaches identify cellular processes influenced by Muscleblind function, whereas in vivo and cell culture experiments define Drosophila troponin T as a new Muscleblind target, reveal a potential involvement of MblC in programmed cell death and recognize the FKRP motif as a putative regulator of MblC function and/or subcellular location in the cell (Vicente-Crespo, 2008).

Using Drosophila as a model organism, this study reports the first screen specifically addressed to identify gene functions related to the biomedically important protein Muscleblind. In support of the relevance of the results, the strong functional conservation between fly and vertebrate Muscleblind proteins is shown. Furthermore, data is presented supporting that Muscleblind can induce apoptosis in vivo in imaginal disc tissue, and a conserved motif in the MblC protein isoform was identified that conferred pro-apoptotic activity in Drosophila cell culture when mutated. Noteworthy, this is the first conserved motif (besides CCCH zinc fingers) that is associated with a particular function in Muscleblind proteins (Vicente-Crespo, 2008).

Whereas most vertebrates include three muscleblind paralogues in their genomes, a single muscleblind gene carries out all muscleblind-related functions in Drosophila. These functions are probably accomplished through alternative splicing, which generates four Muscleblind protein isoforms with different carboxy-terminal regions. An evolutionary analysis was performed with isoform-specific protein sequences in order to assess conservation of alternative splicing within protostomes. MblC-like isoforms have been detected even in the nematodes C. elegans and Ascaris suum but not MblA, B or D, that were only consistently found within Drosophilidae. Interestingly, also vertebrate Mbnl1 genes included MblC-like sequences. This finding, together with previous studies that shown that mblC is the isoform with the strongest activity in a muscleblind mutant rescue experiment and α-actinin minigene splicing assay point to mblC as the isoform performing most of muscleblind functions in the fly. Despite this, Muscleblind isoforms are partially redundant. Both mblA and B partially rescue the embryonic lethality of muscleblind mutant embryos and were able to similarly promote foetal exon exclusion in murine TnnT3 minigene splicing assays. MblD showed no activity in splicing assays or in vivo overexpression experiments. However, we show a marginal increase in cell viability in cell death assays. Using isoform-specific RNAi constructs we plan to re-evaluate the function of Muscleblind isoforms both in vivo and in cell culture (Vicente-Crespo, 2008).

Although the regulation of alternative splicing by Muscleblind proteins is an established fact, the cellular processes in which the protein participates are largely unknown. Genetic screens provide a way to approach those processes as they interrogate a biological system as a whole. Overexpression of MblC in the Drosophila eye originated an externally rough eye phenotype that is temperature sensitive, thus indicating sensitization to the muscleblind dose. A deficiency screen was performed, and several candidate mutations were tested for dominant modification of the phenotype. Nineteen were identifed genes of which more that half can be broadly classified as involved in apoptosis regulation (rpr, th and Traf1), RNA metabolism (Aly, tsu, aret and nonA) or transcription regulation (jumu, amos, Dp, CG15435 and CG15433), whereas the rest do not easily fall into defined classes. muscleblind has been shown to regulate α-actinin and troponinT alternative splicing both in vivo and in cell culture. The genetic interaction with the Drosophila homolog of human splicing factor CUG-BP1 (aret) and nonA supports a functional relationship in flies. The antagonism between MBNL1 and CUG-BP1 has actually been shown in humans, whereas RNA-binding protein NonA might be relevant to Muscleblind sequestration by CUG repeat RNA in flies (Vicente-Crespo, 2008 and references therein).

Reduction of dose of exon junction complex (EJC) components tsunagi and Aly also modify MblC overexpression phenotype. EJC provides a binding platform for factors involved in mRNA splicing, export and non-sense mediated decay (NMD). This suggests a previously unforeseen relationship between Muscleblind and EJC, perhaps helping to couple splicing to mRNA export. Consistently, Aly mutations enhanced a CUG repeat RNA phenotype in the Drosophila eye. A similar coupling between transcription and splicing might explain the identification of a number of transcription factors in the screen. Of these, the effect of jumu alleles in the eye and wing MblC overexpression phenotypes were studied in some detail. Loss of function jumu mutations suppress both wing defects and rough eye, whereas they have no effect on unrelated overexpression phenotypes thus suggesting that the interaction is specific (Vicente-Crespo, 2008).

Mutations in the Drosophila homolog of vertebrate Inhibitor of Apoptosis (Diap1 or thread) dominantly enhanced the rough eye phenotype. Consistently with the specificity of the interaction, a second Drosophila paralog, Diap2, did not interact. Also, a deficiency that removes the Drosophila proapoptotic genes hid, reaper and grim (which inhibit thread) was a dominant suppressor while reaper overexpression in eye disc enhanced the phenotype. Interestingly the human homolog of Drosophila Hsp70Ab, Hsp70, has been related to apoptosis as it directly interacts with Apaf-1 and Apoptosis Inducing Factor (AIF) resulting in the inhibition of caspase-dependent and caspase-independent apoptosis. All these genetic data are consistent with MblC overexpressing eye discs being sensitized to enter apoptosis, although no increase in caspase-3 activation was detected in third instar eye imaginal disc overexpressing MblC (Vicente-Crespo, 2008).

Human MBNL1 and CUB-BP1 cooperate to regulate the splicing of cardiac TroponinT (cTNT). The current study detected splicing defects in Drosophila troponinT mRNA in muscleblind mutant pupae. Interestingly, an abnormal exclusion of exon 3 was detected in muscleblind mutant pupae, encoding a glutamic acid-rich domain homologous to the foetal exon of cTNT regulated by human MBNL1. Drosophila exon 3 is only absent in the troponinT isoform expressed in TDT and IFM muscles and probably confers specific functional properties much like the foetal exon does in humans. This identifies troponinT as a new target of Muscleblind activity in flies (Vicente-Crespo, 2008).

CUG-BP1 protein antagonizes MBNL1 exon choice activity in IR and cTNT pre-mRNAs. Moreover, a genetic interaction has been detected between MblC overexpression and aret loss of function mutations. In order to further characterize the functional interaction between Muscleblind and Bruno proteins, their ability to regulate murine TnnT3 was examined in human cell culture. MblA, B and C showed strong activity on TnnT3 mRNA but no significant activity was detected for any Bruno protein. This shows a strong functional conservation between fly and vertebrate Muscleblind proteins as Drosophila isoforms can act over a murine target in a human environment. In contrast, Bruno proteins might not conserve the regulatory activity over troponinT mRNA described for their vertebrate homologues or at least they were not functional in the cellular environment used in this assay. Because GFP-tagged Bruno proteins were only weakly expressed in HEK cells under the experimental conditions used, the level of expression might be insufficient to overcome endogenous Muscleblind activity in cell culture. Furthermore, Bruno proteins might antagonize Muscleblind on a different subset of RNA targets. Although bruno1 has been shown to regulate splicing of some transcripts in S2 cell culture and Bruno3 binds the same EDEN sequence than human CUG-BP, no in vivo experiments have addressed the functional conservation between fly and vertebrate Brunos. Bruno1 is expressed in the germ line where it acts as translational repressor of oskar and gurken mRNAs (Vicente-Crespo, 2008).

Wing imaginal discs stained with anti-caspase-3 and with TUNEL showed that activation of apoptosis was not general in cells expressing MblC but restricted to defined regions within the disc, in particular the wing blade. The spatial constraints that were observed within the imaginal disc might explain the small effect detected when expressing Muscleblind proteins in S2 cells. MblC might require the presence of other factors to be able to unleash programmed cell death. Alternatively, the level of overexpression may be critical and transfected Muscleblind proteins may not reach a critical threshold in Drosophila S2 cells. MblC activation of apoptosis could reveal a direct regulation of apoptotic genes at RNA level or be an indirect effect. Several apoptotic genes produce pro-apoptotic or anti-apoptotic isoforms depending on the regulation of their alternative splicing. MblC could be similarly regulating protein isoforms originating from one or a number of key apoptotic genes at the level of pre-mRNA splicing. Alternatively, MblC could be regulating isoform ratio of a molecule indirectly related to programmed cell death, for example a cell adhesion molecule causing apoptosis by inefficient cell attachment to the substrate. Furthermore, human MBNL proteins are implicated not only in splicing but also in RNA localization, a process that if conserved in flies can potentially impinge in apoptosis regulation (Vicente-Crespo, 2008).

The analysis of MblC-specific sequence revealed a region conserved in Muscleblind proteins from nematodes to humans. Post-translational prediction programs found a motif (FKRP) weakly resembling a sumoylation target site. However, results in S2 cells suggest that sumoylation, if actually taking place, modifies only a small fraction of MblC proteins. FKRP may alternatively participate in an interaction with a Muscleblind partner potentially regulating activity or location in cell compartments, assist in protein dimerization, or others functions. The FKRP site was mutated and a number of functional assays were performed using the mutant MblC. Whereas MblCK202I excluded foetal exon in TnnT3 minigene splicing assays and bound CUG repeat RNA like its wild type counterpart, the mutant protein showed a different preferential distribution in human cells and significantly increased cell death activation upon overexpression. The mechanism by which the FKRP site influences subcellular distribution and cell death-inducing activities is currently unknown, but nevertheless constitutes the first motif, other than zinc fingers, that is associated with a function within Muscleblind proteins (Vicente-Crespo, 2008).

Proteomic survey reveals altered energetic patterns and metabolic failure prior to retinal degeneration

Inherited mutations that lead to misfolding of the visual pigment rhodopsin (Rho) are a prominent cause of photoreceptor neuron (PN) degeneration and blindness. How Rho proteotoxic stress progressively impairs PN viability remains unknown. To identify the pathways that mediate Rho toxicity in PNs, a comprehensive proteomic profiling of retinas was performed from Drosophila transgenics expressing Rh1P37H, the equivalent of mammalian RhoP23H, the most common Rho mutation linked to blindness in humans. Profiling of young Rh1P37H retinas revealed a coordinated upregulation of energy-producing pathways and attenuation of energy-consuming pathways involving target of rapamycin (TOR) signaling, which was reversed in older retinas at the onset of PN degeneration. The relevance of these metabolic changes to PN survival was probed by using a combination of pharmacological and genetic approaches. Chronic suppression of TOR signaling, using the inhibitor rapamycin, strongly mitigated PN degeneration, indicating that TOR signaling activation by chronic Rh1P37H proteotoxic stress is deleterious for PNs. Genetic inactivation of the endoplasmic reticulum stress-induced JNK/TRAF1 axis as well as the APAF-1/caspase-9 axis, activated by damaged mitochondria, dramatically suppressed Rh1P37H-induced PN degeneration, identifying the mitochondria as novel mediators of Rh1P37H toxicity. It is thus proposed that chronic Rh1P37H proteotoxic stress distorts the energetic profile of PNs leading to metabolic imbalance, mitochondrial failure, and PN degeneration and therapies normalizing metabolic function might be used to alleviate Rh1P37H toxicity in the retina. This study offers a glimpse into the intricate higher order interactions that underlie PN dysfunction and provides a useful resource for identifying other molecular networks that mediate Rho toxicity in PNs (Griciuc, 2014).


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TNF-receptor-associated factor 1: Biological Overview | Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation

date revised: 10 March 2014

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