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

doi:10.1016/j.celrep.2019.08.055

Viral MLKL Homologs Subvert Necroptotic Cell Death by Sequestering Cellular RIPK3

Cell Rep. 2019 Sep 24;28(13):3309-3319.e5. doi: 10.1016/j.celrep.2019.08.055.

Authors

Emma J Petrie¹, Jarrod J Sandow², Wil I L Lehmann², Lung-Yu Liang², Diane Coursier³, Samuel N Young³, Wilhelmus J A Kersten³, Cheree Fitzgibbon³, André L Samson², Annette V Jacobsen², Kym N Lowes², Amanda E Au², Hélène Jousset Sabroux², Najoua Lalaoui², Andrew I Webb², Guillaume Lessene⁴, Gerard Manning⁵, Isabelle S Lucet², James M Murphy⁶

Affiliations

¹ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia. Electronic address: petrie.e@wehi.edu.au.
² The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
³ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
⁴ 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.
⁵ Department of Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, CA 94080, USA.
⁶ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia. Electronic address: jamesm@wehi.edu.au.

PMID: 31553902
DOI: 10.1016/j.celrep.2019.08.055

Abstract

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.

Keywords: MLKL; RIPK3; innate immunity; necroptosis; poxvirus; programmed necrosis; pseudokinase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Death
Humans
Immunity, Innate
Mice
Necrosis
Protein Kinases / metabolism*
Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*

Substances

MLKL protein, human
Protein Kinases
RIPK3 protein, human
Receptor-Interacting Protein Serine-Threonine Kinases