Viral modulation of programmed necrosis
William J Kaiser1, Jason W Upton, Edward S Mocarski
1Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
Abstract:
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.
Insights
Viruses and host defenses engage in an evolutionary arms race, with caspase 8 acting as a central regulator of apoptosis and programmed necrosis. This balance shapes host-pathogen interactions.
Area of Science:
- Cellular biology
- Immunology
- Virology
Background:
- Apoptosis and programmed necrosis are key host defense mechanisms against viral infections.
- Viruses have evolved countermeasures, including B cell leukemia (BCL)2-like suppressors, to evade intrinsic apoptosis.
- Extrinsic apoptosis and programmed necrosis evolved as subsequent defense strategies.
Purpose of the Study:
- To elucidate the evolutionary interplay between host cell death pathways and viral countermeasures.
- To understand the role of caspase 8 as a central regulator in this dialog.
Main Methods:
- Comparative analysis of apoptosis and programmed necrosis pathways.
- Examination of viral strategies to inhibit host cell death.
- Investigating the activation triggers of receptor interacting protein (RIP)3 kinase (RIPK3).
Main Results:
- Intrinsic apoptosis is modulated by viral BCL2-like suppressors.
- Extrinsic apoptosis, regulated by caspase 8, emerged to bypass intrinsic apoptosis suppressors.
- Programmed necrosis, involving RIPK3, acts as a backup to extrinsic apoptosis when caspase 8 or RIP1 is inhibited.
- Caspase 8 functions as a critical 'supersensor' controlling both cell death pathways.
Conclusions:
- The evolution of cell death pathways is driven by viral pressures.
- Caspase 8 plays a pivotal role in orchestrating apoptosis and programmed necrosis.
- Understanding this balance is crucial for developing antiviral strategies.
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