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Viral infection and the evolution of caspase 8-regulated apoptotic and necrotic death pathways

Edward S Mocarski1, Jason W Upton2, William J Kaiser1

  • 1Department of Microbiology and Immunology, Emory Vaccine Center, 1462 Clifton Rd. NE, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

Nature Reviews. Immunology
|December 24, 2011
PubMed

Insights

Mammals need caspase 8 to control receptor-interacting protein kinases (RIP1 and RIP3) during development. This interaction is crucial for host defense against intracellular pathogens like herpesviruses.

Area of Science:

  • Cellular biology
  • Immunology
  • Developmental biology

Background:

  • Pathogens exploit both apoptotic and necrotic cell death pathways.
  • Caspase 8 and RIP kinases (RIP1, RIP3) are key regulators of these pathways.
  • Their interplay in host defense is not fully understood.

Purpose of the Study:

  • To investigate the co-regulation of caspase 8-dependent apoptosis and RIP kinase-dependent necrosis.
  • To elucidate the role of this interplay in embryonic development and host defense.

Main Methods:

  • Utilizing genetically modified mouse models deficient in FADD or caspase 8.
  • Assessing the impact of RIP1 or RIP3 elimination on survival and development.
  • Analyzing the crosstalk between apoptotic and necrotic cell death pathways.

Main Results:

  • Midgestational death in FADD- or caspase 8-deficient mice was rescued by RIP1 or RIP3 ablation.
  • This indicates a critical co-regulatory relationship between caspase 8 and RIP kinases.
  • Caspase 8 activity is required to suppress RIP1 and RIP3 during embryogenesis.

Conclusions:

  • Mammalian development and host defense against pathogens like herpesviruses rely on caspase 8 to suppress RIP kinases.
  • There is a fundamental co-regulation between apoptotic and necrotic cell death pathways.
  • This study reveals a more intertwined relationship between these cell death processes than previously known.

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