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Human cytomegalovirus protein pUL36: a dual cell death pathway inhibitor

Fletcher-Etherington, Alice, Nobre, Luis, Nightingale, Katie, Antrobus, Robin, Nichols, Jenna, Davison, Andrew J., Stanton, Richard J. ORCID: and Weekes, Michael P. 2020. Human cytomegalovirus protein pUL36: a dual cell death pathway inhibitor. Proceedings of the National Academy of Sciences 117 (31) , 18771 - 18779. 10.1073/pnas.2001887117

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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: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Publisher: National Academy of Sciences
ISSN: 0027-8424
Funders: MRC
Date of First Compliant Deposit: 22 July 2020
Date of Acceptance: 25 June 2020
Last Modified: 08 May 2023 02:28

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