Viral MLKL Homologs Subvert Necroptotic Cell Death by Sequestering Cellular RIPK3
Emma J. Petrie,
Jarrod J. Sandow,
Wil I.L. Lehmann,
Lung-Yu Liang,
Diane Coursier,
Samuel N. Young,
Wilhelmus J.A. Kersten,
Cheree Fitzgibbon,
André L. Samson,
Annette V. Jacobsen,
Kym N. Lowes,
Amanda E. Au,
Hélène Jousset Sabroux,
Najoua Lalaoui,
Andrew I. Webb,
Guillaume Lessene,
Gerard Manning,
Isabelle S. Lucet,
James M. Murphy
Affiliations
Emma J. Petrie
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia; Corresponding author
Jarrod J. Sandow
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia
Wil I.L. Lehmann
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia
Lung-Yu Liang
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia
Diane Coursier
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
Samuel N. Young
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
Wilhelmus J.A. Kersten
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
Cheree Fitzgibbon
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
André L. Samson
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia
Annette V. Jacobsen
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia
Kym N. Lowes
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia
Amanda E. Au
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia
Hélène Jousset Sabroux
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia
Najoua Lalaoui
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia
Andrew I. Webb
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia
Guillaume Lessene
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia; Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, VIC 3052, Australia
Gerard Manning
Department of Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, CA 94080, USA
Isabelle S. Lucet
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia
James M. Murphy
The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia; Corresponding author
Summary: 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. : 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. Keywords: poxvirus, innate immunity, pseudokinase, necroptosis, programmed necrosis, MLKL, RIPK3
