Structure and Interactions of the Ubiquitin-Conjugating Enzyme Variant Human Uev1a:  Implications for Enzymatic Synthesis of Polyubiquitin Chains†,‖

OTUB1 is a deubiquitinating enzyme that cleaves Lys-48–linked polyubiquitin chains and also regulates ubiquitin signaling through a unique, noncatalytic mechanism. OTUB1 binds to a subset of E2 ubiquitin-conjugating enzymes and inhibits their activity by trapping the E2∼ubiquitin thioester and preventing ubiquitin transfer. The same set of E2s stimulate the deubiquitinating activity of OTUB1 when the E2 is not charged with ubiquitin. Previous studies have shown that, in cells, OTUB1 binds to E2-conjugating enzymes of the UBE2D (UBCH5) and UBE2E families, as well as to UBE2N (UBC13). Cellular roles have been identified for the interaction of OTUB1 with UBE2N and members of the UBE2D family, but not for interactions with UBE2E E2 enzymes. We report here a novel role for OTUB1–E2 interactions in modulating E2 protein ubiquitination. We observe that Otub1−/− knockout mice exhibit late-stage embryonic lethality. We find that OTUB1 depletion dramatically destabilizes the E2-conjugating enzyme UBE2E1 (UBCH6) in both mouse and human OTUB1 knockout cell lines. Of note, this effect is independent of the catalytic activity of OTUB1, but depends on its ability to bind to UBE2E1. We show that OTUB1 suppresses UBE2E1 autoubiquitination in vitro and in cells, thereby preventing UBE2E1 from being targeted to the proteasome for degradation. Taken together, we provide evidence that OTUB1 rescues UBE2E1 from degradation in vivo.

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Ube2v1, a ubiquitin‐conjugating enzyme variant, is an essential component for the ubiquitination of MEKK1 in FGF2‐mediated signaling in endothelial cells

The FASEB Journal ◽

10.1096/fasebj.2019.33.1_supplement.465.6 ◽

2019 ◽

Vol 33 (S1) ◽

Author(s):

Yung Joon Yoo ◽

Muthumumar Elangovan ◽

Suk Won Jin

Keyword(s):

Endothelial Cells ◽

Essential Component ◽

Ubiquitin Conjugating Enzyme ◽

Enzyme Variant ◽

Conjugating Enzyme

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A Homologue of CROC-1 in a Ciliated Protist (Sterkiella histriomuscorum) Testifies to the Ancient Origin of the Ubiquitin-conjugating Enzyme Variant Family

Molecular Biology and Evolution ◽

10.1093/oxfordjournals.molbev.a003980 ◽

2002 ◽

Vol 19 (1) ◽

pp. 39-48 ◽

Cited By ~ 14

Author(s):

Eduardo Villalobo ◽

Loïc Morin ◽

Clara Moch ◽

Rachel Lescasse ◽

Michelle Hanna ◽

...

Keyword(s):

Ubiquitin Conjugating Enzyme ◽

Enzyme Variant ◽

Conjugating Enzyme

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Distinct regulation of Ubc13 functions by the two ubiquitin-conjugating enzyme variants Mms2 and Uev1A

The Journal of Cell Biology ◽

10.1083/jcb.200502113 ◽

2005 ◽

Vol 170 (5) ◽

pp. 745-755 ◽

Cited By ~ 105

Author(s):

Parker L. Andersen ◽

Honglin Zhou ◽

Landon Pastushok ◽

Trevor Moraes ◽

Sean McKenna ◽

...

Keyword(s):

Nuclear Factor Κb ◽

Cysteine Residue ◽

Physical Interaction ◽

Polyubiquitin Chains ◽

Active Site Cysteine ◽

Cellular Processes ◽

Damage Repair ◽

Ubiquitin Conjugating Enzyme ◽

Active Site Cysteine Residue ◽

Conjugating Enzyme

Ubc13, a ubiquitin-conjugating enzyme (Ubc), requires the presence of a Ubc variant (Uev) for polyubiquitination. Uevs, although resembling Ubc in sequence and structure, lack the active site cysteine residue and are catalytically inactive. The yeast Uev (Mms2) incites noncanonical Lys63-linked polyubiquitination by Ubc13, whereas the increased diversity of Uevs in higher eukaryotes suggests an unexpected complication in ubiquitination. In this study, we demonstrate that divergent activities of mammalian Ubc13 rely on its pairing with either of two Uevs, Uev1A or Mms2. Structurally, we demonstrate that Mms2 and Uev1A differentially modulate the length of Ubc13-mediated Lys63-linked polyubiquitin chains. Functionally, we describe that Ubc13–Mms2 is required for DNA damage repair but not nuclear factor κB (NF-κB) activation, whereas Ubc13–Uev1A is involved in NF-κB activation but not DNA repair. Our finding suggests a novel regulatory mechanism in which different Uevs direct Ubcs to diverse cellular processes through physical interaction and alternative polyubiquitination.

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