Cnidaria XIAP activates caspase-mediated cell death.

Area of Science:

• Cell Biology
• Evolutionary Biology
• Biochemistry

Background:

• Vertebrate X-linked inhibitor of apoptosis (XIAP) inhibits apoptosis by binding caspases via baculovirus IAP repeat (BIR) domains and mediating ubiquitination via RING and ubiquitin-associated (UBA) domains.
• XIAP is known to inhibit apoptosis in invertebrates like arthropods, but its role in basal metazoans remains unexplored.

Purpose of the Study:

• To investigate the biological activity and evolutionary role of XIAP in basal metazoans, specifically focusing on jellyfish (Aurelia coerulea) XIAP (AcXIAP).
• To elucidate the mechanism by which AcXIAP interacts with and modulates caspase activity.

Main Methods:

• Examined the biological activity of AcXIAP and XIAP from other non-bilaterians (hydra, coral, sponge).
• Analyzed AcXIAP's domain structure, identifying three BIR domains and one RING domain, but lacking a UBA domain.
• Assessed AcXIAP's effect on jellyfish caspases and performed XIAP knockdown experiments in hydra.

Main Results:

• AcXIAP enhanced the apoptosis-inducing activity of all four identified Aurelia coerulea caspases.
• AcXIAP activated caspases through BIR domain binding and stabilization, and RING domain-mediated, lysine-independent ubiquitination of the caspase p20 subunit.
• Similar caspase-activating properties were found in XIAP from hydra, coral, and sponge, with XIAP knockdown in hydra reducing apoptosis.

Conclusions:

• XIAP in basal metazoans, like Cnidaria, exhibits an unconventional function and working mechanism compared to vertebrates.
• The findings shed light on the functional and structural evolution of XIAP, highlighting its ancient role in apoptosis regulation.
• AcXIAP's mechanism involves BIR-mediated caspase binding/stabilization and RING-mediated ubiquitination, distinct from the UBA-dependent mechanisms in some other organisms.