Species-Specific Inhibition of Necroptosis by HCMV UL36

Viral infection activates cellular antiviral defenses including programmed cell death (PCD). Many viruses, particularly those of the <i>Herpesviridae</i> family, encode cell death inhibitors that antagonize different forms of PCD. While some viral inhibitors are broadly active in cells o...

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Autores principales:	Elena Muscolino, Claudia Castiglioni, Renke Brixel, Giada Frascaroli, Wolfram Brune
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	apoptosis necroptosis RIPK1 RIPK3 MLKL UL36 Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/78a69bb246cd4b8da573c3db788e7c44
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spelling	oai:doaj.org-article:78a69bb246cd4b8da573c3db788e7c442021-11-25T19:12:35ZSpecies-Specific Inhibition of Necroptosis by HCMV UL3610.3390/v131121341999-4915https://doaj.org/article/78a69bb246cd4b8da573c3db788e7c442021-10-01T00:00:00Zhttps://www.mdpi.com/1999-4915/13/11/2134https://doaj.org/toc/1999-4915Viral infection activates cellular antiviral defenses including programmed cell death (PCD). Many viruses, particularly those of the <i>Herpesviridae</i> family, encode cell death inhibitors that antagonize different forms of PCD. While some viral inhibitors are broadly active in cells of different species, others have species-specific functions, probably reflecting the co-evolution of the herpesviruses with their respective hosts. Human cytomegalovirus (HCMV) protein UL36 is a dual cell death pathway inhibitor. It blocks death receptor-dependent apoptosis by inhibiting caspase-8 activation, and necroptosis by binding to the mixed lineage kinase domain-like (MLKL) protein and inducing its degradation. While UL36 has been shown to inhibit apoptosis in human and murine cells, the specificity of its necroptosis-inhibiting function has not been investigated. Here we show that UL36 interacts with both human and murine MLKL, but has a higher affinity for human MLKL. When expressed by a recombinant mouse cytomegalovirus (MCMV), UL36 caused a modest reduction of murine MLKL levels but did not inhibit necroptosis in murine cells. These data suggest that UL36 inhibits necroptosis, but not apoptosis, in a species-specific manner, similar to ICP6 of herpes simplex virus type 1 and MC159 of molluscum contagiosum virus. Species-specific necroptosis inhibition might contribute to the narrow host range of these viruses.Elena MuscolinoClaudia CastiglioniRenke BrixelGiada FrascaroliWolfram BruneMDPI AGarticleapoptosisnecroptosisRIPK1RIPK3MLKLUL36MicrobiologyQR1-502ENViruses, Vol 13, Iss 2134, p 2134 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	apoptosis necroptosis RIPK1 RIPK3 MLKL UL36 Microbiology QR1-502
spellingShingle	apoptosis necroptosis RIPK1 RIPK3 MLKL UL36 Microbiology QR1-502 Elena Muscolino Claudia Castiglioni Renke Brixel Giada Frascaroli Wolfram Brune Species-Specific Inhibition of Necroptosis by HCMV UL36
description	Viral infection activates cellular antiviral defenses including programmed cell death (PCD). Many viruses, particularly those of the <i>Herpesviridae</i> family, encode cell death inhibitors that antagonize different forms of PCD. While some viral inhibitors are broadly active in cells of different species, others have species-specific functions, probably reflecting the co-evolution of the herpesviruses with their respective hosts. Human cytomegalovirus (HCMV) protein UL36 is a dual cell death pathway inhibitor. It blocks death receptor-dependent apoptosis by inhibiting caspase-8 activation, and necroptosis by binding to the mixed lineage kinase domain-like (MLKL) protein and inducing its degradation. While UL36 has been shown to inhibit apoptosis in human and murine cells, the specificity of its necroptosis-inhibiting function has not been investigated. Here we show that UL36 interacts with both human and murine MLKL, but has a higher affinity for human MLKL. When expressed by a recombinant mouse cytomegalovirus (MCMV), UL36 caused a modest reduction of murine MLKL levels but did not inhibit necroptosis in murine cells. These data suggest that UL36 inhibits necroptosis, but not apoptosis, in a species-specific manner, similar to ICP6 of herpes simplex virus type 1 and MC159 of molluscum contagiosum virus. Species-specific necroptosis inhibition might contribute to the narrow host range of these viruses.
format	article
author	Elena Muscolino Claudia Castiglioni Renke Brixel Giada Frascaroli Wolfram Brune
author_facet	Elena Muscolino Claudia Castiglioni Renke Brixel Giada Frascaroli Wolfram Brune
author_sort	Elena Muscolino
title	Species-Specific Inhibition of Necroptosis by HCMV UL36
title_short	Species-Specific Inhibition of Necroptosis by HCMV UL36
title_full	Species-Specific Inhibition of Necroptosis by HCMV UL36
title_fullStr	Species-Specific Inhibition of Necroptosis by HCMV UL36
title_full_unstemmed	Species-Specific Inhibition of Necroptosis by HCMV UL36
title_sort	species-specific inhibition of necroptosis by hcmv ul36
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/78a69bb246cd4b8da573c3db788e7c44
work_keys_str_mv	AT elenamuscolino speciesspecificinhibitionofnecroptosisbyhcmvul36 AT claudiacastiglioni speciesspecificinhibitionofnecroptosisbyhcmvul36 AT renkebrixel speciesspecificinhibitionofnecroptosisbyhcmvul36 AT giadafrascaroli speciesspecificinhibitionofnecroptosisbyhcmvul36 AT wolframbrune speciesspecificinhibitionofnecroptosisbyhcmvul36
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Species-Specific Inhibition of Necroptosis by HCMV UL36

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