Viral MLKL Homologs Subvert Necroptotic Cell Death by Sequestering Cellular RIPK3
Emma J Petrie1, Jarrod J Sandow1, Wil I L Lehmann1
1The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
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.
Insights
Poxviruses encode MLKL-like proteins that block necroptotic cell death by inhibiting RIPK3 activation. These viral mimics highlight necroptosis's ancient role in immunity against pathogens.
Area of Science:
- Cellular Biology
- Immunology
- Virology
Background:
- Necroptotic cell death is crucial in human diseases and innate immunity.
- The necroptosis pathway involves receptor-interacting protein kinase 3 (RIPK3) and mixed-lineage kinase-domain-like (MLKL).
Purpose of the Study:
- To investigate the function of MLKL-like proteins found in poxvirus genomes.
- To understand the role of these viral proteins in modulating host necroptosis pathways.
Main Methods:
- Identification of MLKL-homologous proteins in poxvirus genomes.
- Expression of viral MLKL-like proteins in human and mouse cells.
- Assays to measure MLKL activation and necroptotic cell death.
Main Results:
- Proteins from BeAn 58058 and Cotia poxviruses, but not swinepox, inhibited MLKL activation and necroptosis.
- Viral MLKL-like proteins acted as dominant-negative inhibitors by sequestering RIPK3.
- This sequestration prevented MLKL engagement and phosphorylation, blocking necroptosis.
Conclusions:
- Necroptosis likely evolved as an ancient defense mechanism against pathogens.
- Poxviruses have evolved to mimic host pseudokinases like MLKL to evade immune responses.
- This viral mimicry expands the known functions of pseudokinases in cellular signaling and host-pathogen interactions.
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