Journal
VIRUSES-BASEL
Volume 13, Issue 11, Pages -Publisher
MDPI
DOI: 10.3390/v13112134
Keywords
apoptosis; necroptosis; RIPK1; RIPK3; MLKL; UL36; M45; ICP6; HCMV; MCMV; herpesvirus
Categories
Funding
- Deutsche Forschungsgemeinschaft [BR 1730/3-2]
- Free and Hanseatic City of Hamburg
- German Federal Ministry of Health
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Viral infection triggers cellular antiviral defenses, including programmed cell death. Some viruses encode cell death inhibitors to counteract various forms of cell death. Human cytomegalovirus protein UL36 inhibits both apoptosis and necroptosis, showing species-specific functions.
Viral infection activates cellular antiviral defenses including programmed cell death (PCD). Many viruses, particularly those of the Herpesviridae 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.
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