Caspase-6 Is a Key Regulator of Innate Immunity, Inflammasome Activation, and Host Defense

Area of Science:

• Immunology
• Cell Biology
• Virology

Background:

• Caspases are key regulators of cell death and immune responses.
• Caspase-6, an executioner caspase, has poorly understood functions beyond apoptosis.
• Its specific roles in innate immunity and inflammasome activation remain largely unexplored.

Purpose of the Study:

• To investigate the role of caspase-6 in innate immunity and inflammasome activation.
• To determine caspase-6's involvement in programmed cell death pathways and host defense against influenza A virus (IAV).
• To elucidate the mechanism of caspase-6 in Z-DNA binding protein 1 (ZBP1)-mediated signaling.

Main Methods:

• Investigated caspase-6's role in inflammasome activation and programmed cell death (pyroptosis, apoptosis, necroptosis - PANoptosis).
• Assessed caspase-6's function in host defense during influenza A virus infection.
• Examined caspase-6's effect on alternatively activated macrophage (AAM) differentiation.
• Analyzed the interaction between caspase-6, RIPK3, and ZBP1 in RIP homotypic interaction motif (RHIM)-dependent complex formation.

Main Results:

• Caspase-6 mediates innate immunity and inflammasome activation.
• Caspase-6 promotes PANoptosis and is essential for host defense against influenza A virus (IAV).
• Caspase-6 facilitates RIPK3-ZBP1 binding via RIPK3, crucial for ZBP1-mediated inflammasome activation.
• Caspase-6 promotes alternatively activated macrophage differentiation.

Conclusions:

• Caspase-6 plays a vital role in ZBP1-mediated inflammasome activation, cell death, and host defense during IAV infection.
• These findings highlight caspase-6 as a potential therapeutic target for infectious diseases, autoinflammatory conditions, and cancer.
• Caspase-6's functions extend beyond apoptosis, encompassing critical roles in immunity and cell death regulation.