The Ubiquitin-conjugating Enzyme (E2) Ube2w Ubiquitinates the N Terminus of Substrates

Scaglione, K. Matthew; Basrur, Venkatesha; Ashraf, Naila S.; Konen, John R.; Elenitoba-Johnson, Kojo S.J.; Todi, Sokol V.; Paulson, Henry L.

doi:10.1074/jbc.c113.477596

Cited by 94 publications

(110 citation statements)

References 36 publications

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“…These results are in good agreement with previous reports of cooperation between Ube2W and Ube2N/Ube2V2 (12,22) and the ability of Ube2W to mediate specific N-terminal ubiquitination of substrates (22)(23)(24). In the absence of Ube2W, Ube2N/Ube2V2 and TRIM21 synthesize unanchored Ub-63 Ub in vitro.…”

Section: Discussionsupporting

confidence: 82%

“…1G). Together, these experiments suggest Ube2N and Ube2W are nonredundant cofactors for both sensing and effector responses of TRIM21, an unexpected observation because Ube2W is reported to anchor polyUb to substrates (22,23) and Ub-63 Ub chains are not thought to recruit proteins to the proteasome (17).…”

Section: Ube2w and Ube2n Are Required For Trim21 Dual Effector And Sementioning

confidence: 99%

“…2E, lane 3). (22)(23)(24). To assess whether TRIM21 is also ubiquitinated by Ube2W independent of lysine residues in vitro, we purified TRIM21 RING-Box proteins bearing lysine-to-arginine substitutions at all six lysine residues in TRIM21 RING-Box : three in the RING domain (Lys45, Lys61, Lys77) and three in the B-Box2 domain (Lys105, Lys108, Lys119).…”

Section: Ube2w and Ube2n Are Required For Trim21 Dual Effector And Sementioning

confidence: 99%

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Sequential ubiquitination and deubiquitination enzymes synchronize the dual sensor and effector functions of TRIM21

Fletcher

Mallery

Watkinson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

110

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Tripartite motif (TRIM) 21 is a cytosolic antibody receptor that neutralizes antibody-coated viruses that penetrate the cell and simultaneously activates innate immunity. Here we show that the conjugation of TRIM21 with K63-linked ubiquitin (Ub-63 Ub) catalyzed by the sequential activity of nonredundant E2 Ub enzymes is required for its dual antiviral functions. TRIM21 is first labeled with monoubiquitin (monoUb) by the E2 Ube2W. The monoUb is a substrate for the heterodimeric E2 Ube2N/Ube2V2, resulting in TRIM21-anchored Ub-63 Ub. Depletion of either E2 abolishes Ub-63 Ub and Ub-48 Ub conjugation of TRIM21, NF-κB signaling, and virus neutralization. The formation of TRIM21-Ub-63 Ub precedes proteasome recruitment, and we identify an essential role for the 19S-resident and degradation-coupled deubiquitinase Poh1 in TRIM21 neutralization, signaling, and cytokine induction. This study elucidates a complex mechanism of step-wise ubiquitination and deubiquitination activities that allows contemporaneous innate immune signaling and neutralization by TRIM21.

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Section: Discussionsupporting

confidence: 82%

Section: Ube2w and Ube2n Are Required For Trim21 Dual Effector And Sementioning

confidence: 99%

Section: Ube2w and Ube2n Are Required For Trim21 Dual Effector And Sementioning

confidence: 99%

See 1 more Smart Citation

Sequential ubiquitination and deubiquitination enzymes synchronize the dual sensor and effector functions of TRIM21

Fletcher

Mallery

Watkinson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

110

160

View full text Add to dashboard Cite

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“…Two reported UBE2W substrates are the neurodegenerative disease proteins Ataxin-3 and Tau (17,18), suggesting a potentially important role for UBE2W in brain. To eliminate UBE2W expression selectively in the central nervous system (CNS), we crossed Ube2w Flox/Flox mice with Nestin promoter-driven, Cre recombinase-expressing mice.…”

Section: Isoform 1 Is the Major Expressed Ube2w Isoform In Mouse-mentioning

confidence: 99%

“…UBE2W is the only E2 known to mediate N-terminal ubiquitination (16,17). It can function with various ubiquitin ligases, including the C terminus of Hsc-70-interacting protein and the BRCA1-BARD1 complex (18 -20), to monoubiquitinate select substrates at their N termini with an apparent preference for substrates having intrinsically disordered N termini (21).…”

mentioning

confidence: 99%

Loss of the Ubiquitin-conjugating Enzyme UBE2W Results in Susceptibility to Early Postnatal Lethality and Defects in Skin, Immune, and Male Reproductive Systems

Wang¹,

Merillat²,

Vincent

et al. 2016

Journal of Biological Chemistry

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UBE2W ubiquitinates N termini of proteins rather than internal lysine residues, showing a preference for substrates with intrinsically disordered N termini. The in vivo functions of this intriguing E2, however, remain unknown. We generated Ube2w germ line KO mice that proved to be susceptible to early postnatal lethality without obvious developmental abnormalities. Although the basis of early death is uncertain, several organ systems manifest changes in Ube2w KO mice. Newborn Ube2w KO mice often show altered epidermal maturation with reduced expression of differentiation markers. Mirroring higher UBE2W expression levels in testis and thymus, Ube2w KO mice showed a disproportionate decrease in weight of these two organs (ϳ50%), suggesting a functional role for UBE2W in the immune and male reproductive systems. Indeed, Ube2w KO mice displayed sustained neutrophilia accompanied by increased G-CSF signaling and testicular vacuolation associated with decreased fertility. Proteomic analysis of a vulnerable organ, presymptomatic testis, showed a preferential accumulation of disordered proteins in the absence of UBE2W, consistent with the view that UBE2W preferentially targets disordered polypeptides. These mice further allowed us to establish that UBE2W is ubiquitously expressed as a single isoform localized to the cytoplasm and that the absence of UBE2W does not alter cell viability in response to various stressors. Our results establish that UBE2W is an important, albeit not essential, protein for early postnatal survival and normal functioning of multiple organ systems.

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Does N‐Terminal Protein Acetylation Lead to Protein Degradation?

et al. 2019

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The N-end rule denotes the relationship between the identity of the amino-terminal residue of a protein and its in vivo half-life. Since its discovery in 1986, the N-end rule has generally been described by a defined set of rules for determining whether an amino-terminal residue is stabilizing or not. However, recent studies are revealing that this N-end rule (or N-degron concept) is less straightforward than previously appreciated. For instance, it is unveiled that N-terminal acetylation of N-terminal residues may create a degradation signal (Ac-degron) that promotes the degradation of target proteins. A recent high-throughput dissection of degrons in yeast proteins amino termini intriguingly suggested that the hydrophobicity of amino-terminal residues-but not the N-terminal acetylation status-may be the indispensable feature of amino-terminal degrons. Herein, these recent advances in N-terminal acetylation and the complexity of N-terminal degradation signals in the context of the N-degron pathway are analyzed.

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The Ubiquitin-conjugating Enzyme (E2) Ube2w Ubiquitinates the N Terminus of Substrates

Cited by 94 publications

References 36 publications

Sequential ubiquitination and deubiquitination enzymes synchronize the dual sensor and effector functions of TRIM21

Sequential ubiquitination and deubiquitination enzymes synchronize the dual sensor and effector functions of TRIM21

Loss of the Ubiquitin-conjugating Enzyme UBE2W Results in Susceptibility to Early Postnatal Lethality and Defects in Skin, Immune, and Male Reproductive Systems

Does N‐Terminal Protein Acetylation Lead to Protein Degradation?

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