Apoptosis inhibitor 5 is an endogenous inhibitor of caspase‐2 Academic Article uri icon

abstract

  • 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.

authors

  • Imre, Gergely
  • Berthelet, Jean
  • Heering, Jan
  • Kehrloesser, Sebastian
  • Melzer, Inga Maria
  • Lee, Byung Il
  • Thiede, Bernd
  • Dötsch, Volker
  • Rajalingam, Krishnaraj

publication date

  • 2017