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.

A functional genomics screen identifying blood cell development genes inDrosophilaby undergraduates participating in a course-based research experience

“…Prp19 itself is an E3 ubiquitin ligase, the activity of which is required for the proper assembly and activation of the spliceosome ( Chan 2003 ; de Moura et al 2018 ). While function of Prp19 in lymph gland hematopoiesis remains unclear, Prp19 has been shown to be required for proper Ras/MAP kinase signaling in the Drosophila eye, and for proper Notch signaling in the C. elegans germline ( Ashton-Beaucage et al 2014 ; Gutnik et al 2018 ). Furthermore, mutation of Prp19 was previously shown to cause a reduction in the crystal cell lineage during head mesoderm hematopoiesis in Drosophila embryos ( Milchanowski et al 2004 ).…”

Redundant mechanisms regulating the proliferation vs. differentiation balance in the C. elegans germline

“…TEG-1 is homologous to CD2BP2, which has been implicated in U4/U6.U5 tri-snRNP formation (Wang et al, 2012(Wang et al, , 2017, TEG-4 is homologous to subunit 3 of SF3b (Mantina et al, 2009), and PRP-17 is homologous to the PRP17/CDC40 pre-mRNA splicing factor (Kerins et al, 2010). Other splicing factors have also been identified as being involved through other genetic screens or directly testing for potential involvement, including mog-1, mog-4, mog-5 (masculinization of germline), cyn-4/mog-6 and prp-19 Puoti and Kimble, 1999;Belfiore et al, 2004;Kerins et al, 2010;Gutnik et al, 2018). Importantly, reduction or loss of these factors alone does not result in a disruption of the proliferation vs. differentiation decision.…”

Decoding lifespan secrets: the role of the gonad in Caenorhabditis elegans aging

“…Removing these somatic cells causes premature differentiation of the germline stem cells into gametes ( Kimble and White, 1981 ). glp-1 , a member of the Notch receptor family ( Yochem et al, 1988 ; Austin and Kimble, 1989 ; Kimble and Simpson, 1997 ) expressed in the germline ( Cinquin et al, 2015 ; Gutnik et al, 2018 ; Sorensen et al, 2020 ), is required to keep stem cells in an undifferentiated state. Thus, glp-1 loss-of-function mutants mimic the Z2/Z3-ablated animals because both lack proliferating and undifferentiated germ cells.…”