Human cytomegalovirus protein RL1 degrades the antiviral factor SLFN11 via recruitment of the CRL4 E3 ubiquitin ligase complex

Nightingale, K. et al. (2022) Human cytomegalovirus protein RL1 degrades the antiviral factor SLFN11 via recruitment of the CRL4 E3 ubiquitin ligase complex. Proceedings of the National Academy of Sciences of the United States of America, 119(6), e2108173119. (doi: 10.1073/pnas.2108173119) (PMID:35105802) (PMCID:PMC8832970)

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Abstract

Human cytomegalovirus (HCMV) is an important human pathogen and a paradigm of viral immune evasion, targeting intrinsic, innate, and adaptive immunity. We have employed two orthogonal multiplexed tandem mass tag-based proteomic screens to identify host proteins down-regulated by viral factors expressed during the latest phases of viral infection. This approach revealed that the HIV-1 restriction factor Schlafen-11 (SLFN11) was degraded by the poorly characterized, late-expressed HCMV protein RL1, via recruitment of the Cullin4-RING E3 Ubiquitin Ligase (CRL4) complex. SLFN11 potently restricted HCMV infection, inhibiting the formation and spread of viral plaques. Overall, we show that a restriction factor previously thought only to inhibit RNA viruses additionally restricts HCMV. We define the mechanism of viral antagonism and also describe an important resource for revealing additional molecules of importance in antiviral innate immunity and viral immune evasion.

Item Type:Articles
Additional Information:This research was funded in part by a Wellcome Trust Senior Clinical Research Fellowship 108070/Z/15/Z (to M.P.W.); Medical Research Council Project Grants MR/P001602/1 (to E.C.Y.W.) and MR/S00971X/1 and MR/V000489/1 (to R.J.S. and E.C.Y.W.); and Medical Research Council Programme Grant MC_UU_12014/3 (to A.J.D.).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Davison, Professor Andrew and Suarez, Dr Nicolas and Nichols, Mrs Jenna
Authors: Nightingale, K., Potts, M., Hunter, L. M., Fielding, C. A., Zerbe, C. M., Fletcher-Etherington, A., Nobre, L., Wang, E. C. Y., Strang, B. L., Houghton, J. W., Antrobus, R., Suarez, N. M., Nichols, J., Davison, A. J., Stanton, R. J., and Weekes, M. P.
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:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
ISSN:0027-8424
ISSN (Online):1091-6490
Published Online:01 February 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Proceedings of the National Academy of Sciences of the United States of America 119(6): e2108173119
Publisher Policy:Reproduced under a Creative Commons License
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
172630003Persistent Infections (Programme 2)Andrew DavisonMedical Research Council (MRC)MC_UU_12014/3III - Centre for Virus Research