UBQLN2 facilitates degradation of the retrotransposon protein PEG10 via UBE3A activity
Roberts, J. E.; Huynh, P. T.; Whiteley, A. M.
Show abstract
Ubiquilins are a family of extrinsic ubiquitin receptors that are thought to facilitate protein degradation by shuttling proteins to the proteasome. However, the defining characteristics of Ubiquilin clients, and the steps of Ubiquilin-mediated degradation, have been elusive. Previously, we showed Ubiquilin 2 (UBQLN2) regulates the proteasomal degradation of PEG10, a unique virus-like protein which comes in two forms: a gag protein which is not regulated by UBQLN2, and a gag-pol protein which is dependent on UBQLN2. Here, we refine the model of Ubiquilin activity through the UBQLN2-mediated degradation of PEG10. UBQLN2 binding did not ensure degradation, and was independent of client ubiquitination, though ubiquitination of key lysine residues was necessary for gag-pol proteolysis. Ubiquitination was dependent on the E3 ubiquitin ligase UBE3A, which was surprisingly unable to regulate gag-pol in the absence of UBQLN2. Together, we have established a stepwise model of UBQLN2-mediated degradation that represents a new perspective on Ubiquilin function. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=183 SRC="FIGDIR/small/646022v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@21f763org.highwire.dtl.DTLVardef@1f88cdborg.highwire.dtl.DTLVardef@e79156org.highwire.dtl.DTLVardef@f6d6ce_HPS_FORMAT_FIGEXP M_FIG Graphical abstract: Working model of UBQLN2 and UBE3A-mediated degradation of PEG10 gag-pol. In an apparent first step, UBQLN2 binds both PEG10 gag and gag-pol through STI1:gag-dominated interactions, independent of PEG10 ubiquitination. Either concurrently or immediately thereafter, UBQLN2 binds to UBE3A through interactions facilitated by UBA:AZUL domain binding, though other protein domains contribute to this interaction as well. UBE3A and other unknown E3 ligases contribute to the ubiquitination of gag-pol on lysine residues of both the gag and pol regions, which is necessary for proteasomal degradation. The proteasome also interacts with UBQLN2:UBE3A:PEG10, likely through UBL domain interactions with the regulatory cap. Inhibition of E1 ubiquitin activation through TAK243, UBE3A activity with siRNA, or proteasomal degradation with Bortezomib all interfere with UBQLN2-mediated PEG10 degradation. C_FIG
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Global proteomics of Ubqln2-based murine models of ALS 96%
- The X-linked intellectual disability gene product and E3 ubiquitin ligase KLHL15 degrades doublecortin proteins to constrain neuronal dendritogenesis 94%
- Transcription factor LSF facilitiates lysine methylation of α-tubulin by microtubule-associated SET8 93%
Similar papers in this journal
- ER-embedded UBE2J1/RNF26 ubiquitylation complex in spatio-temporal control of the endolysosomal pathway 95%
- The selective autophagy receptor p62 and the heat shock protein HSP27 facilitate lysophagy via the formation of phase-separated condensates 94%
- USP9X deubiquitylates DVL2 to regulate WNT pathway specification 94%
Similar papers in this journal
- Small molecule correctors divert CFTR-F508del from ERAD by stabilizing sequential folding states 95%
- Loss of Grp170 results in catastrophic disruption of endoplasmic reticulum functions 94%
- AP-4 regulates neuronal lysosome composition, function and transport via regulating export of critical lysosome receptor proteins at the trans-Golgi network 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.