Direct and Indirect Control of Mitogen-activated Protein Kinase Pathway-associated Components, BRAP/IMP E3 Ubiquitin Ligase and CRAF/RAF1 Kinase, by the Deubiquitylating Enzyme USP15

Abstract

Background: Deubiquitylases (DUBs) oppose the action of E3-ligases and influence key signalling pathways.Results: USP15 stabilizes the E3 ligase BRAP/IMP, regulates CRAF expression, and is a positive regulator of MEK.Conclusion: USP15 is a positive regulator of the MAPK pathway while stabilizing the E3 ligase BRAP/IMP.Significance: Evidence is provided for novel modes of MAPK pathway regulation by DUBs.

The U4/U6 Recycling Factor SART3 Has Histone Chaperone Activity and Associates with USP15 to Regulate H2B Deubiquitination

“…Usp15 has been implicated in the deubiquitination of a wide variety of substrates, including proteins in the TGF␤-signaling pathway and several E3 ligases (57)(58)(59)(60)(61)(62). Although Usp4 and Usp15 sequences are very similar, they most likely perform overlapping, but non-identical, functions.…”

The Deubiquitylase USP2 Regulates the LDLR Pathway by Counteracting the E3-Ubiquitin Ligase IDOL

“…28,32 Regulation of E3 ligases by deubiquitylasemediated deubiquitylation has been previously reported and represents an emerging concept in E3 control. 17,[19][20][21] Previous reports indicated that deubiquitylases stabilize E3s by limiting their autoubiquitylation. Consequently, deubiquitylation of E3s acts to enhance substrate ubiquitylation.…”

“…3,22 Our prey library contained 61 deubiquitylases, representing 77% of known active mammalian deubiquitylases, previously used in a systematic deubiquitylase-E3 interaction screen (Online Table I). 20 This screen failed to identify any LDLR-tail-interacting deubiquitylases (Online Figure IA). However, the assay identified the deubiquitylase USP2-69 isoform (referred to further as USP2), as an interacting partner of the full-length IDOL protein (Online Table I).…”

“…16,18 Adding to the complexity, recent studies indicate that in addition to removing or remodeling ubiquitin (chains) from ubiquitylated substrates, deubiquitylases may also act directly on E3s, thereby modifying the stability and activity of the latter. 19,20 Characterizing the deubiquitylase-E3 interactome thus represents an important step in understanding how E3s are themselves regulated by ubiquitylation. 17,21 Whether deubiquitylases play a role in cholesterol metabolism is largely unknown.…”

Layers of DUB regulation

“…Here, the N-terminal TRAF domain of USP7 binds small peptide motifs in its targets EBNA-1 (Epstein-Barr nuclear antigen 1), p53 and MDM2 (Mouse double minute 2 homolog) to facilitate their deubiquitylation ( Figure 1) [23,24]. USP15 uses its DUSP-Ubl domain to recruit and deubiquitylate the E3 ligase BRCA1-associated protein (BRAP) [25], while the H2A deubiquitinase USP3 requires its intact Zinc finger domain to bind H2A [26].…”