Human cytomegalovirus protein pUL36: A dual cell death pathway inhibitor.

Proceedings of the National Academy of Sciences of the United States of America
Alice Fletcher-EtheringtonMichael P Weekes

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.

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Citations

Sep 4, 2020·Journal of Virology·Aaron M AltmanGary C Chan
Jan 20, 2021·Cell Death and Differentiation·Yanxiang MengJames M Murphy
Feb 17, 2021·Cell Death and Differentiation·André L SamsonJames M Murphy
Apr 1, 2021·Cellular & Molecular Immunology·Damien BerthelootBernardo S Franklin
May 1, 2021·International Journal of Molecular Sciences·Zhongjie YuBin Wang
Jun 16, 2021·Annual Review of Virology·Alice Fletcher-Etherington, Michael P Weekes
Sep 20, 2021·Journal of Molecular Biology·Lam Nhat Nguyen, Thirumala-Devi Kanneganti

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Datasets Mentioned

BETA
PXD017279

Methods Mentioned

BETA
footprinting
immunoprecipitation
co-IP
electrophoresis
PCR
transfection
Assay

Software Mentioned

Plotter
Image Studio Lite

Related Concepts

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis