Apoptosis inhibitor 5 is an endogenous inhibitor of caspase‐2

• DOI: 10.15252/embr.201643744
• Publication Date: 2017-03-24T00:13:29Z
• Authors: Gergely Imre; Jean Berthelet; Jan Heering; Sebastian Kehrloe...; Inga Maria Melzer; Byung Il Lee; Bernd Thiede; Volker Dötsch; Krishnaraj Rajali...
• Keywords: Center (category theory)

Caspases are key enzymes responsible for mediating apoptotic cell death. Across species, caspase-2 is the most conserved caspase and stands out due to unique features. Apart from cell death, caspase-2 also regulates autophagy, genomic stability and ageing. Caspase-2 requires dimerization for its activation which is primarily accomplished by recruitment to high molecular weight protein complexes in cells. Here, we demonstrate that apoptosis inhibitor 5 (API5/AAC11) is an endogenous and direct inhibitor of caspase-2. API5 protein directly binds to the caspase recruitment domain (CARD) of caspase-2 and impedes dimerization and activation of caspase-2. Interestingly, recombinant API5 directly inhibits full length but not processed caspase-2. Depletion of endogenous API5 leads to an increase in caspase-2 dimerization and activation. Consistently, loss of API5 sensitizes cells to caspase-2-dependent apoptotic cell death. These results establish API5/AAC-11 as a direct inhibitor of caspase-2 and shed further light onto mechanisms driving the activation of this poorly understood caspase.