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Human cytomegalovirus protein pUL36: a dual cell death pathway inhibitor

ABSTRACT: Human cytomegalovirus (HCMV) is an important human pathogen and a paradigm of intrinsic, innate and adaptive viral immune evasion. Here, we employ multiplexed tandem mass tag-based proteomics to characterise 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 pro-caspase 8, we define pUL36 as a multifunctional inhibitor of both apoptotic and necroptotic cell death.

INSTRUMENT(S): Orbitrap Fusion Lumos, Orbitrap Fusion

ORGANISM(S): Cytomegalovirus Homo Sapiens (human)

TISSUE(S): Cell Culture, Fibroblast

SUBMITTER: Michael Weekes

LAB HEAD: Michael Weekes

PROVIDER: PXD017279 | Pride | 2020-07-10

REPOSITORIES: Pride

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			Action	DRS
	Fletcher-EtheringtonetalPeptides.xlsx	Xlsx
	Fletcher-EtheringtonetalProteins.xlsx	Xlsx
	PRIDEsubmission-Detailsofsamples.docx	Other
	WCL1_A1_run1.raw	Raw
	WCL1_B1_run1.raw	Raw

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