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 |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Davison, Professor Andrew and Nichols, Mrs Jenna |
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 > 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: | 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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