Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 32, Pages 10014-10019Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1507534112
Keywords
TRIM21; NF-kappa B; Ube2W; Ube2N/Ube2V2; Poh1
Categories
Funding
- Medical Research Council [U105181010]
- European Research Council [281627IAI]
- Medical Research Council [MC_U105181010] Funding Source: researchfish
- MRC [MC_U105181010] Funding Source: UKRI
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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-kappa B 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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