Inhibitor of apoptosis proteins are substrates for the mitochondrial serine protease Omi/HtrA2.
The mature serine protease Omi/HtrA2 is released from the mitochondria into the cytosol during apoptosis. Suppression of Omi/HtrA2 by RNA interference in human cell lines reduces cell death in response to TRAIL and etoposide. In contrast, ectopic expression of mature wildtype Omi/HtrA2, but not an active site mutant, induces potent caspase activation and apoptosis. In vitro assays demonstrated that Omi/HtrA2 could degrade inhibitor of apoptosis proteins (IAPs). Consistent with this observation, increased expression of Omi/HtrA2 in cells increases degradation of XIAP, while suppression of Omi/HtrA2 by RNA interference has an opposite effect. Combined, our data demonstrate that IAPs are substrates for Omi/HtrA2, and their degradation could be a mechanism by which the mitochondrially released Omi/HtrA2 activates caspases during apoptosis.
Srinivasula
Srinivasa M
SM
Center for Apoptosis Research and the Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Gupta
Sanjeev
S
Datta
Pinaki
P
Zhang
ZhiJia
Z
Hegde
Ramesh
R
Cheong
NaEun
N
Fernandes-Alnemri
Teresa
T
Alnemri
Emad S
ES
D017209:Apoptosis; D001483:Base Sequence; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D017931:DNA Primers; D004789:Enzyme Activation; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D008928:Mitochondria / Q000201:enzymology*; D024101:Mitochondrial Proteins; D011506:Proteins / Q000378:metabolism*; D034622:RNA Interference; D012697:Serine Endopeptidases / Q000378:metabolism*; D013379:Substrate Specificity; D051636:X-Linked Inhibitor of Apoptosis Protein
D017931:DNA Primers; D024101:Mitochondrial Proteins; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2; D020169:Caspases