Viral modulation of programmed necrosis

•Evolution of host cell death pathways was driven by virus-encoded cell death suppressors.•Caspase 8 regulates extrinsic apoptosis as well as programmed necrosis.•RIP3 (also called RIPK3) is the key mediator of programmed necrosis.•Programmed necrosis involves RIP3 RHIM-dependent interactions with RIP1, DAI or TRIF.•Programmed necrosis is suppressed by RHIM inhibitor vIRA encoded by MCMV.

Apoptosis and programmed necrosis balance each other as alternate first line host defense pathways against which viruses have evolved countermeasures. Intrinsic apoptosis, the critical programmed cell death pathway that removes excess cells during embryonic development and tissue homeostasis, follows a caspase cascade triggered at mitochondria and modulated by virus-encoded anti-apoptotic B cell leukemia (BCL)2-like suppressors. Extrinsic apoptosis controlled by caspase 8 arose during evolution to trigger executioner caspases directly, circumventing viral suppressors of intrinsic (mitochondrial) apoptosis and providing the selective pressure for viruses to acquire caspase 8 suppressors. Programmed necrosis likely evolved most recently as a ‘trap door’ adaptation to extrinsic apoptosis. Receptor interacting protein (RIP)3 kinase (also called RIPK3) becomes active when either caspase 8 activity or polyubiquitylation of RIP1 is compromised. This evolutionary dialog implicates caspase 8 as a ‘supersensor’ alternatively activating and suppressing cell death pathways.