Abstract
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.
Highlights
It has been shown that UL36 inhibits necroptosis by interacting with human MLKL (hMLKL) [24]
We wanted to test whether UL36 can interact with both human and murine mixed lineage kinase domain-like (MLKL)
We show that the Human cytomegalovirus (HCMV) UL36 protein, which inhibits necroptosis in human cells, is incapable of preventing necroptosis in murine cells
Summary
Herpesviruses are important human pathogens widely spread among the human population. They cause long-life infections characterized by phases of latency and reactivation [1,2]. The host cell recognizes the infection and triggers innate immune responses that lead to the production of inflammatory cytokines, type I interferon (IFN), and various molecules that activate the adaptive immune response [3]. Cellular defense mechanisms that restrict viral replication are activated, such as the shutoff of protein translation, the degradation of viral components via the proteasome or lysosome pathways, and the induction of cell death [4,5,6]
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