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

Fletcher, A. J., Mallery, D. L., Watkinson, R. E., Dickson, C. F. and James, L. C. (2015) Sequential ubiquitination and deubiquitination enzymes synchronize the dual sensor and effector functions of TRIM21. Proceedings of the National Academy of Sciences, 112(32), pp. 10014-10019. (doi: 10.1073/pnas.1507534112) (PMID:26150489) (PMCID:PMC4538650)

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Abstract

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-63Ub) 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-63Ub. Depletion of either E2 abolishes Ub-63Ub and Ub-48Ub conjugation of TRIM21, NF-κB signaling, and virus neutralization. The formation of TRIM21-Ub-63Ub 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.

Item Type:Articles
Additional Information:This work was funded by the Medical Research Council (U105181010) and the European Research Council (281627IAI).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Fletcher, Dr Adam
Authors: Fletcher, A. J., Mallery, D. L., Watkinson, R. E., Dickson, C. F., and James, L. C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Proceedings of the National Academy of Sciences
Publisher:National Academy of Sciences
ISSN:0027-8424
ISSN (Online):1091-6490
Published Online:06 July 2015

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