JIL-1 kinase: Biological Overview | Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation | References

Gene name - JIL-1 kinase

Synonyms - 2Ab17

Cytological map position - 68A3--4

Function - signal transduction

Keywords - chromatin, dosage compensation

Symbol - JIL-1

FlyBase ID: FBgn0020412

Genetic map position - 3-

Classification - protein serine/threonine kinase

Cellular location - nuclear

NCBI link: Entrez Gene
JIL1 orthologs: Biolitmine
Recent literature
Li, Y., Wang, C., Cai, W., Sengupta, S., Zavortink, M., Deng, H., Girton, J., Johansen, J. and Johansen, K. M. (2017). H2Av facilitates H3S10 phosphorylation but is not required for heat shock-induced chromatin decondensation or transcriptional elongation. Development 144(18): 3232-3240. PubMed ID: 28807902
A model has been proposed in which JIL-1 kinase-mediated H3S10 and H2Av phosphorylation is required for transcriptional elongation and heat shock-induced chromatin decondensation. However, this study shows that although H3S10 phosphorylation is indeed compromised in the H2Av null mutant, chromatin decondensation at heat shock loci is unaffected in the absence of JIL-1 as well as of H2Av and that there is no discernable decrease in the elongating form of RNA polymerase II in either mutant. Furthermore, mRNA for the major heat shock protein Hsp70 is transcribed at robust levels in both H2Av and JIL-1 null mutants. Using a different chromatin remodeling paradigm that is JIL-1 dependent, evidence is provided that ectopic tethering of JIL-1 and subsequent H3S10 phosphorylation recruits PARP-1 to the remodeling site independently of H2Av phosphorylation. These data strongly suggest that H2Av or H3S10 phosphorylation by JIL-1 is not required for chromatin decondensation or transcriptional elongation in Drosophila.
Albig, C., Wang, C., Dann, G. P., Wojcik, F., Schauer, T., Krause, S., Maenner, S., Cai, W., Li, Y., Girton, J., Muir, T. W., Johansen, J., Johansen, K. M., Becker, P. B. and Regnard, C. (2019). JASPer controls interphase histone H3S10 phosphorylation by chromosomal kinase JIL-1 in Drosophila. Nat Commun 10(1): 5343. PubMed ID: 31767855
In flies, the chromosomal kinase JIL-1 is responsible for most interphase histone H3S10 phosphorylation and has been proposed to protect active chromatin from acquiring heterochromatic marks, such as dimethylated histone H3K9 (H3K9me2) and HP1. This study shows that JIL-1's targeting to chromatin depends on a PWWP domain-containing protein JASPer (JIL-1 Anchoring and Stabilizing Protein; CG7946). JASPer-JIL-1 (JJ)-complex is the major form of kinase in vivo and is targeted to active genes and telomeric transposons via binding of the PWWP domain of JASPer to H3K36me3 nucleosomes, to modulate transcriptional output. JIL-1 and JJ-complex depletion in cycling cells lead to small changes in H3K9me2 distribution at active genes and telomeric transposons. Finally, interactors of the endogenous JJ-complex were identified, and it is proposed that JIL-1 not only prevents heterochromatin formation but also coordinates chromatin-based regulation in the transcribed part of the genome.
Dou, K., Liu, Y., Zhang, Y., Wang, C., Huang, Y. and Zhang, Z. Z. (2020). Drosophila P75 safeguards oogenesis by preventing H3K9me2 spreading. J Genet Genomics. PubMed ID: 32499180
Serving as a host factor for human immunodeficiency virus (HIV) integration, LEDGF/p75 has been under extensive study as a potential target for therapy. However, as a highly conserved protein, its physiological function remains to be thoroughly elucidated. This study characterized the molecular function of dP75, the Drosophila homolog of LEDGF/p75, during oogenesis. dP75 binds to transcriptionally active chromatin with its PWWP domain. The C-terminus integrase-binding domain-containing region of dP75 physically interacts with the histone kinase Jil-1 and stabilizes it in vivo. Together with Jil-1, dP75 prevents the spreading of the heterochromatin mark-H3K9me2-onto genes required for oogenesis and piRNA production. Without dP75, ectopical silencing of these genes disrupts oogenesis, activates transposons, and causes animal sterility. It is proposed that dP75, the homolog of an HIV host factor in Drosophila, partners with and stabilizes Jil-1 to ensure gene expression during oogenesis by preventing ectopic heterochromatin spreading.

A monoclonal antibody, mAb2A, detects a protein (Johansen, 1996a; Johansen, 1996b) that is chromosomally localized throughout the cell cycle (Jin, 1999). JIL-1, found to be the protein detected by mAb2A, is a chromosomal kinase that is upregulated almost twofold on the male X chromosome in Drosophila. Phylogenetic analysis suggests that JIL-1 together with the related human MSKs define a separate family of tandem kinases. JIL-1 undergoes autophosphorylation and phosphorylation of Histone H3 in vitro. It is suggested that JIL-1 is part of the dosage compensation apparatus. JIL-1 colocalizes and physically interacts with male specific lethal (MSL) dosage compensation complex proteins. Ectopic expression of the MSL complex directed by MSL2 in females causes a concomitant upregulation of JIL-1 to the female X that is abolished in msl mutants unable to assemble the complex. Thus, these results strongly indicate JIL-1 associates with the MSL complex and further suggests that JIL-1 functions in signal transduction pathways regulating chromatin structure (Jin, 1999 and 2000).

JIL-1's distribution pattern was analyzed in confocal images of larval polytene chromosomes. JIL-1 localizes to hundreds of sites along the polytene chromosome that correspond to interband regions. Since interbands arise from partial unfolding of the 30 nm chromatin fiber and have been proposed to be the sites of actively transcribed genes, these findings suggest that JIL-1 may be involved in gene activity potentially by regulation of chromatin structure via histone phosphorylation. However, JIL-1 is not required at all locations of decondensed chromatin since there are interband regions that do not show JIL-1 labeling. The expression of JIL-1 on female and male X chromosomes was tested in relation to JIL-1 expression on autosomes. In female polytene squashes there is no significant difference between autosomal and X chromosome staining intensity, whereas in males, a highly statistically significant difference is found between autosomal and X-chromosomal staining intensities. There is an almost 2-fold increase in the level of JIL-1 on the Drosophila male X chromosome compared to autosomes, which correlates well with the roughly 2-fold increased transcription level on this chromosome due to dosage compensation mechanisms. This finding also raises the intriging possiblity that JIL-1 plays a functional role in dosage compensation (Jin, 1999).

In an effort to determine the molecular basis for dosage compensation in Drosophila, a number of genetic screens were performed that have identified several genes necessary for achieving equal levels of most X-linked transcription. The products of these genes assemble into a complex termed MSL (male specific lethal) that is thought to be responsible for targeting a histone acetyltransferase that acetylates histone H4 (H4Ac16) to the upregulated male X chromosome, which in turn leads to altered chromatin structure (Smith, 2000). The MSL holocomplex is known to include MSL1, a novel acidic protein; MSL2, a RING finger protein; MSL3, a chromodomain protein; MLE, an RNA helicase; MOF, a histone acetyltransferase, and two nontranslated RNAs, roX1 and roX2. The MSL complex preferentially associates at hundreds of sites on the male X but fails to assemble in females due to a Sex lethal-regulated block in translation of the MSL2 subunit. The MSL complex colocalizes with the H4Ac16 pattern on the male X chromosome, and absence of any of the MSL complex subunits prevents both MSL complex assembly as well as the enhanced H4Ac16 modification on the male X chromosome. Furthermore, studies have shown that ectopic expression of MSL2 in females results in formation and targeting of the MSL complex to both female X chromosomes with a concomitant upregulation of H4Ac16 levels (Jin, 2000 and references therein).

In order to understand the mechanisms of dosage compensation occurring in Drosophila it is necessary to identify all the components of the MSL complex and to determine how they may interact to mediate upregulation of transcription on the male X. JIL-1 colocalizes with the MSL complex proteins on the male X; JIL-1 can molecularly interact with MSL complex proteins; ectopic expression of MSL2 in females causes a concomitant upregulation of JIL-1 to the female X; this upregulation is abolished in msl mutants that are unable to assemble the complex. Thus, these results strongly indicate that JIL-1 can associate with the MSL dosage compensation complex. The ability of JIL-1 to phosphorylate histone H3 in vitro (Jin, 1999) further suggests a model where JIL-1's role in the MSL complex is to assist in regulating transcription possibly through modification of chromatin (Jin, 2000).

The MSL complex is believed to promote dosage compensation in males by targeting MOF, the histone acetylase responsible for the increased H4Ac16 modification found on the male X chromosome (Smith, 2000). This modification is thought to lead to a more diffuse chromatin structure and enhanced accessibility of the DNA for transcription. However, it is becoming increasingly evident that in addition to acetylation, phosphorylation may also play a key role not only at the level of modulation of transcription factor activity, but also more generally at the level of chromatin structure. For example, histone H3 phosphorylation has been found to occur in a small subset of nucleosomes in mitogenically stimulated cells. This phosphorylation appears to be regulated by mitogen-activated signal transduction cascades indicating a direct link between signal transduction pathways and chromatin structure. JIL-1 has been shown to phosphorylate histone H3 in vitro (Jin, 1999) suggesting that the MSL complex may affect chromatin structure not only by histone acetylation, but also by histone phosphorylation. However, the finding that JIL-1 interacts with the MSL complex through its kinase domains also raises the possibility that one or more of the proteins in the MSL complex itself could be a substrate for JIL-1. Regardless of whether the substrate(s) for JIL-1 is histones or components of the MSL complex (or both) it is likely that the JIL-1 kinase serves as a regulator of MSL complex function through site-specific phosphorylation (Jin, 2000).

The finding that JIL-1 associates with the MSL complex is based on physical interaction assays such as coimmunoprecipitation and GST pull-down experiments. These approaches require a fairly stable interaction between JIL-1 and the MSL complex making it unlikely that this association depends on the presence of the roX RNAs. This is in contrast to the MLE product that is not found as part of the MSL complex during chromatographic separation, a finding consistent with it being the only one of the known MSL complex proteins to be lost from the male X chromosomes upon treatment with RNase. Moreover, the finding that addition of GST-JIL-1 fusion protein to S2 cell extracts can be used to pull down the MSL complex indicates that this association can occur in vitro and suggests that the JIL-1 kinase can interact with the preassembled MSL complex. However, since this preassembled complex may already contain endogenous JIL-1 it does not address whether the formation of the MSL complex requires the presence of JIL-1 protein or whether JIL-1 is present in the MSL complex in stoichiometric amounts (Jin, 2000).

In contrast to the other MSL complex proteins, JIL-1 is also present in female chromosomes and male autosomes (Jin, 1999), all of which are void of MSL complexes. Future experiments will determine whether JIL-1's more general distribution on the autosomes and on the female X chromosomes may reflect JIL-1's participation in other transcriptional regulator complexes. The deployment of certain proteins into several different chromatin remodeling complexes is emerging as a common theme in the composition of various chromatin remodeling machines and may be a way to accomplish hierarchical levels of gene regulation. It has been shown that JIL-1 associates with at least one known chromatin remodeling machine, the MSL complex, suggesting a direct link between the JIL-1 kinase and the signal transduction pathways regulating transcription and chromatin structure (Jin, 2000).


cDNA clone length - 6.4 kb

Bases in 5' UTR - 1010

Bases in 3' UTR - 1886


Amino Acids - 1207

Structural Domains

A monoclonal antibody, mAb2A, was used to screen a lambda gt11 genomic Drosophila expression library. A partial clone identified in this expression screen was subsequently used to probe embryonic and ovary-specific cDNA libraries, resulting in isolation of several overlapping cDNAs from both developmental stages spanning approximately 6.5 kb. The encoded protein contains two tandemly arranged serine/threonine kinase domains. Based on this tandem kinase domain structure, which is reminiscent of the JAK family of tyrosine kinases, the protein has been named JIL-1. The NH2-terminal domain contains an asparagine-rich stretch (9 out of 10 residues) and an alanine-rich stretch (16 residues). In addition, JIL-1 contains a bipartite nuclear localization signal starting at position 58. Three regions characterized by a low hydrophobicity index and high proline, glutamic acid, aspartic acid, serine, and threonine content are similar to PEST sequences that have been implicated in targeting proteins for rapid turnover (Jin, 1999).

The two kinase domains of JIL-1, KDI and KDII, were compared with all sequences in the current databases in order to identify the most related sequences. KDII is not closely related to any other kinase family; however, KDI has the highest sequence identity with the first kinase domain of a novel protein tandem kinase in human reported in two recent studies called mitogen- and stress-activated kinase, MSK1 (Deak, 1998), or RSK-like protein kinase, RLPK. Whereas JIL-1 is 63% identical in KDI to MSK1, it is only 47% identical to Drosophila RSK. In KDII, JIL-1 is 32% and 28% identical to the second kinase domain in MSK1 and Drosophila RSK, respectively, a level of shared residues reflecting the general level of conserved features among kinase domains. Compared to these other tandem kinases, JIL-1 shows extended NH2- and COOH-terminal domains. To further determine the evolutionary relationship between JIL-1 and other protein kinases, phylogenetic trees were constructed based on maximum parsimony. The phylogenetic analysis indicates that JIL-1 is grouped with 95% bootstrap support with human MSK1 and MSK2 in a monophyletic clade that is distinct from the RSK, S6, and RAC kinase families and their Drosophila homologs. Consequently, these data suggest that JIL-1 is the Drosophila representative of a novel tandem serine/threonine kinase family, which it defines together with MSK1 and MSK2. Interestingly, this phylogenetic analysis also suggests that the S6 kinases, which are single-domain kinases, may have evolved from tandem kinases by a deletion of the second kinase domain (Jin, 1999).

JIL-1: Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation | References

date revised: 2 November 2000

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