Trivalent RING assembly on retroviral capsids activates TRIM5 ubiquitination and innate immune signaling

Fletcher, A. J., Vaysburd, M., Maslen, S., Zeng, J., Skehel, J. M., Towers, G. J. and James, L. C. (2018) Trivalent RING assembly on retroviral capsids activates TRIM5 ubiquitination and innate immune signaling. Cell Host and Microbe, 24(6), 761-775.e6. (doi: 10.1016/j.chom.2018.10.007) (PMID:30503508) (PMCID:PMC6299210)

Abstract

Summary: TRIM5 is a RING domain E3 ubiquitin ligase with potent antiretroviral function. TRIM5 assembles into a hexagonal lattice on retroviral capsids, causing envelopment of the infectious core. Concomitantly, TRIM5 initiates innate immune signaling and orchestrates disassembly of the viral particle, yet how these antiviral responses are regulated by capsid recognition is unclear. We show that hexagonal assembly triggers N-terminal polyubiquitination of TRIM5 that collectively drives antiviral responses. In uninfected cells, N-terminal monoubiquitination triggers non-productive TRIM5 turnover. Upon TRIM5 assembly on virus, a trivalent RING arrangement allows elongation of N-terminally anchored K63-linked ubiquitin chains (N-K63-Ub). N-K63-Ub drives TRIM5 innate immune stimulation and proteasomal degradation. Inducing ubiquitination before TRIM5 assembly triggers premature degradation and ablates antiviral restriction. Conversely, driving N-K63 ubiquitination after TRIM5 assembly enhances innate immune signaling. Thus, the hexagonal geometry of TRIM5’s antiviral lattice converts a capsid-binding protein into a multifunctional antiviral platform.

• Item Type: Articles
• Additional Information: L.C.J. received funding from the Medical Research Council (UK; U105181010 ) and through a Wellcome Trust Investigator Award; G.J.T. received funding through a Wellcome Trust Senior Biomedical Research Fellowship and the European Research Council grant agreement number 339223 ; and A.J.F., M.V., S.M., and J.M.S. were all supported by the Medical Research Council.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Fletcher, Dr Adam
• Authors: Fletcher, A. J., Vaysburd, M., Maslen, S., Zeng, J., Skehel, J. M., Towers, G. J., and James, L. C.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: Cell Host and Microbe
• Publisher: Cell Press
• ISSN: 1931-3128
• ISSN (Online): 1934-6069
• Copyright Holders: Crown Copyright © 2018
• First Published: First published in Cell Host and Microbe 24(6):761-775.e6
• Publisher Policy: Reproduced under a Creative Commons Licence