Viral MLKL Homologs Subvert Necroptotic Cell Death by Sequestering Cellular RIPK3

• Published in: Cell reports (Cambridge) Vol. 28; no. 13; pp. 3309 - 3319.e5
• Main Authors: Petrie, Emma J., Sandow, Jarrod J., Lehmann, Wil I.L., Liang, Lung-Yu, Coursier, Diane, Young, Samuel N., Kersten, Wilhelmus J.A., Fitzgibbon, Cheree, Samson, André L., Jacobsen, Annette V., Lowes, Kym N., Au, Amanda E., Jousset Sabroux, Hélène, Lalaoui, Najoua, Webb, Andrew I., Lessene, Guillaume, Manning, Gerard, Lucet, Isabelle S., Murphy, James M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.09.2019; Elsevier
• Subjects: innate immunity; MLKL; necroptosis; poxvirus; programmed necrosis; pseudokinase; RIPK3; programmed necrosis; innate immunity; MLKL; RIPK3; poxvirus; pseudokinase; necroptosis
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.08.055

Necroptotic cell death has been implicated in many human pathologies and is thought to have evolved as an innate immunity mechanism. The pathway relies on two key effectors: the kinase receptor-interacting protein kinase 3 (RIPK3) and the terminal effector, the pseudokinase mixed-lineage kinase-domain-like (MLKL). We identify proteins with high sequence similarity to the pseudokinase domain of MLKL in poxvirus genomes. Expression of these proteins from the BeAn 58058 and Cotia poxviruses, but not swinepox, in human and mouse cells blocks cellular MLKL activation and necroptotic cell death. We show that viral MLKL-like proteins function as dominant-negative mimics of host MLKL, which inhibit necroptosis by sequestering RIPK3 via its kinase domain to thwart MLKL engagement and phosphorylation. These data support an ancestral role for necroptosis in defense against pathogens. Furthermore, mimicry of a cellular pseudokinase by a pathogen adds to the growing repertoire of functions performed by pseudokinases in signal transduction. [Display omitted] •Some poxviruses encode proteins with homology to mammalian MLKL pseudokinase domains•BAV and Cotia viral MLKL proteins inhibit necroptotic death of human and mouse cells•These viral MLKL proteins target RIPK3 to block activation of cellular MLKL•Viral MLKL proteins inhibit RIPK3 via species-specific mechanisms Petrie et al. identify proteins encoded by some poxviruses with homology to the pseudokinase domain of the terminal necroptosis effector, MLKL. Via species-specific mechanisms, viral MLKL proteins block necroptotic death in human and mouse cells by sequestering RIPK3 to prevent phosphorylation and activation of MLKL.