Viral MLKL homologs subvert necroptotic cell death by sequestering cellular RIPK3
- Petrie, EJ; Sandow, JJ; Lehmann, WIL; Liang, LY; Coursier, D; Young, SN; Kersten, WJA; Fitzgibbon, C; Samson, AL; Jacobsen, AV; Lowes, KN; Au, AE; Jousset Sabroux, H; Lalaoui, N; Webb, AI; Lessene, G; Manning, G; Lucet, IS; Murphy, JM;
Publication Year 2019-09-24, Volume 28, Issue #13, Page 3309-3319 e5
- Journal Title
- Cell Reports
- Publication Type
- Journal Article
- 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.
- WEHI Research Division(s)
- Inflammation; Advanced Technology And Biology; Chemical Biology
- PubMed ID
- Publisher's Version
- Open Access at Publisher's Site
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2019-10-23 02:22:54Last Modified: 2019-10-23 02:45:43