Human cytomegalovirus protein pUL36: a dual cell death pathway inhibitor

Fletcher-Etherlington, A., Nobre, L., Nightingale, K., Antrobus, R., Nichols, J. , Davison, A. J. , Stanton, R. J. and Weekes, M. P. (2020) Human cytomegalovirus protein pUL36: a dual cell death pathway inhibitor. Proceedings of the National Academy of Sciences of the United States of America, 117(31), pp. 18771-18779. (doi: 10.1073/pnas.2001887117) (PMID:32690704)

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Abstract

Human cytomegalovirus (HCMV) is an important human pathogen and a paradigm of intrinsic, innate, and adaptive viral immune evasion. Here, we employed multiplexed tandem mass tag-based proteomics to characterize host proteins targeted for degradation late during HCMV infection. This approach revealed that mixed lineage kinase domain-like protein (MLKL), a key terminal mediator of cellular necroptosis, was rapidly and persistently degraded by the minimally passaged HCMV strain Merlin but not the extensively passaged strain AD169. The strain Merlin viral inhibitor of apoptosis pUL36 was necessary and sufficient both to degrade MLKL and to inhibit necroptosis. Furthermore, mutation of pUL36 Cys131 abrogated MLKL degradation and restored necroptosis. As the same residue is also required for pUL36-mediated inhibition of apoptosis by preventing proteolytic activation of procaspase-8, we define pUL36 as a multifunctional inhibitor of both apoptotic and necroptotic cell death.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Nichols, Mrs Jenna and Davison, Professor Andrew
Authors: Fletcher-Etherlington, A., Nobre, L., Nightingale, K., Antrobus, R., Nichols, J., Davison, A. J., Stanton, R. J., and Weekes, M. P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
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:20 July 2020
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Proceedings of the National Academy of Sciences of the United States of America 117(31): 18771-18779
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
656321Genomics of human cytomegalovirusAndrew DavisonMedical Research Council (MRC)MC_UU_12014/3MVLS III - CENTRE FOR VIRUS RESEARCH