Dataset Information

PRP-19, a conserved pre-mRNA processing factor and E3 ubiquitin ligase, inhibits the nuclear accumulation of GLP-1/Notch intracellular domain.

ABSTRACT: The Notch signalling pathway is a conserved and widespread signalling paradigm, and its misregulation has been implicated in numerous disorders, including cancer. The output of Notch signalling depends on the nuclear accumulation of the Notch receptor intracellular domain (ICD). Using the Caenorhabditis elegans germline, where GLP-1/Notch-mediated signalling is essential for maintaining stem cells, we monitored GLP-1 in vivo We found that the nuclear enrichment of GLP-1 ICD is dynamic: while the ICD is enriched in germ cell nuclei during larval development, it is depleted from the nuclei in adult germlines. We found that this pattern depends on the ubiquitin proteolytic system and the splicing machinery and, identified the splicing factor PRP-19 as a candidate E3 ubiquitin ligase required for the nuclear depletion of GLP-1 ICD.

SUBMITTER: Gutnik S

PROVIDER: S-EPMC6078339 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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PRP-19, a conserved pre-mRNA processing factor and E3 ubiquitin ligase, inhibits the nuclear accumulation of GLP-1/Notch intracellular domain.

Gutnik Silvia S Thomas Yann Y Guo Yanwu Y Stoecklin Janosch J Neagu Anca A Pintard Lionel L Merlet Jorge J Ciosk Rafal R

Biology open 20180716 7

The Notch signalling pathway is a conserved and widespread signalling paradigm, and its misregulation has been implicated in numerous disorders, including cancer. The output of Notch signalling depends on the nuclear accumulation of the Notch receptor intracellular domain (ICD). Using the <i>Caenorhabditis elegans</i> germline, where GLP-1/Notch-mediated signalling is essential for maintaining stem cells, we monitored GLP-1 <i>in vivo</i> We found that the nuclear enrichment of GLP-1 ICD is dyna ...[more]

PMID: 30012553

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Project description:The PINK1 (phosphatase and tensin homologue-induced putative kinase 1)/Parkin-dependent mitochondrial quality control pathway mediates the clearance of damaged organelles, but appears to be disrupted in Parkinson's disease (PD) [Springer and Kahle (2011) Autophagy 7, 266-278]. Upon mitochondrial stress, PINK1 activates the E3 ubiquitin (Ub) ligase Parkin through phosphorylation of the Ub-like (UBL) domain of Parkin and of the small modifier Ub itself at a conserved residue [Sauvé and Gehring (2014) Cell Res. 24, 1025-1026]. Recently resolved partial crystal structures of Parkin showed a 'closed', auto-inhibited conformation, consistent with its notoriously weak enzymatic activity at steady state [Wauer and Komander (2013) EMBO J. 32, 2099-2112; Riley et al. (2013) Nat. Commun. 4, 1982; Trempe et al. (2013) Science 340, 1451-1455; Spratt et al. (2013) Nat. Commun. 4, 1983]. It has thus become clear that Parkin must undergo major structural rearrangements in order to unleash its catalytic functions. Recent published findings derived from X-ray structures and molecular modelling present a complete structural model of human Parkin at an all-atom resolution [Caulfield et al. (2014) PLoS Comput. Biol. 10, e1003935]. The results of the combined in silico simulations-based and experimental assay-based study indicates that PINK1-dependent Ser65 phosphorylation of Parkin is required for its activation and triggering of 'opening' conformations. Indeed, the obtained structures showed a sequential release of Parkin's intertwined domains and allowed docking of an Ub-charged E2 coenzyme, which could enable its enzymatic activity. In addition, using cell-based screening, select E2 enzymes that redundantly, cooperatively or antagonistically regulate Parkin's activation and/or enzymatic functions at different stages of the mitochondrial autophagy (mitophagy) process were identified [Fiesel et al. (2014) J. Cell Sci. 127, 3488-3504]. Other work that aims to pin-point the particular pathogenic dysfunctions of Parkin mis-sense mutations have been recently disseminated (Fabienne C. Fiesel, Thomas R. Caulfield, Elisabeth L. Moussaud-Lamodiere, Daniel F.A.R. Dourado, Kotaro Ogaki, Owen A. Ross, Samuel C. Flores, and Wolfdieter Springer, submitted). Such a structure-function approach provides the basis for the dissection of Parkin's regulation and a targeted drug design to identify small-molecule activators of this neuroprotective E3 Ub ligase.

Dataset Information

PRP-19, a conserved pre-mRNA processing factor and E3 ubiquitin ligase, inhibits the nuclear accumulation of GLP-1/Notch intracellular domain.

Publications

PRP-19, a conserved pre-mRNA processing factor and E3 ubiquitin ligase, inhibits the nuclear accumulation of GLP-1/Notch intracellular domain.

Similar Datasets

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