Apoptosis inhibitor 5 is an endogenous inhibitor of caspase-2.
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.
MSU-FZI, Institute of Immunology, University Medical Center Mainz, JGU, Mainz, Germany.
Gergely
G
Imre
MSU-FZI, Institute of Immunology, University Medical Center Mainz, JGU, Mainz, Germany.
Jean
J
Berthelet
Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany.
Jan
J
Heering
Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany.
Sebastian
S
Kehrloesser
MSU-FZI, Institute of Immunology, University Medical Center Mainz, JGU, Mainz, Germany.
Inga Maria
IM
Melzer
Division of Convergence Technology, Biomolecular Function Research Branch, National Cancer Center, Goyang-si, Gyeonggi-do, Korea.
Byung Il
BI
Lee
Department of Biosciences, University of Oslo, Oslo, Norway.
Bernd
B
Thiede
Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany.
Volker
V
Dötsch
MSU-FZI, Institute of Immunology, University Medical Center Mainz, JGU, Mainz, Germany krishna@uni-mainz.de.|UCT, Mainz, German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
Krishnaraj
0000-0002-4175-9633
K
Rajalingam
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy; D053143:Caspase 2 / Q000737:chemistry / Q000378:metabolism*; D000071476:Caspase Activation and Recruitment Domain; D061945:Caspase Inhibitors / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D013058:Mass Spectrometry; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization
C108386:API5 protein, human; D051017:Apoptosis Regulatory Proteins; D061945:Caspase Inhibitors; D009687:Nuclear Proteins; C490360:CASP2 protein, human; D053143:Caspase 2; D003546:Cysteine Endopeptidases
apoptosis; apoptosis inhibitor 5; caspase‐2; cell death; pore‐forming toxins