The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a reaper-like motif.
The inhibitor-of-apoptosis proteins (IAPs) play a critical role in the regulation of apoptosis by binding and inhibiting caspases. Reaper family proteins and Smac/DIABLO use a conserved amino-terminal sequence to bind to IAPs in flies and mammals, respectively, blocking their ability to inhibit caspases and thus promoting apoptosis. Here we have identified the serine protease Omi/HtrA2 as a second mammalian XIAP-binding protein with a Reaper-like motif. This protease autoprocesses to form a protein with amino-terminal homology to Smac/DIABLO and Reaper family proteins. Full-length Omi/HtrA2 is localized to mitochondria but fails to interact with XIAP. Mitochondria also contain processed Omi/HtrA2, which, following apoptotic insult, translocates to the cytosol, where it interacts with XIAP. Overexpression of Omi/HtrA2 sensitizes cells to apoptosis, and its removal by RNA interference reduces cell death. Omi/HtrA2 thus extends the set of mammalian proteins with Reaper-like function that are released from the mitochondria during apoptosis.
Martins
L Miguel
LM
Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom.
Iaccarino
Ingram
I
Tenev
Tencho
T
Gschmeissner
Stephen
S
Totty
Nicholas F
NF
Lemoine
Nicholas R
NR
Savopoulos
John
J
Gray
Carol W
CW
Creasy
Caretha L
CL
Dingwall
Colin
C
Downward
Julian
J
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D017209:Apoptosis; D001665:Binding Sites; D029721:Drosophila Proteins; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D008928:Mitochondria / Q000201:enzymology; D024101:Mitochondrial Proteins; D008969:Molecular Sequence Data; D010455:Peptides / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000737:chemistry / Q000502:physiology*; D051636:X-Linked Inhibitor of Apoptosis Protein
D029721:Drosophila Proteins; D024101:Mitochondrial Proteins; D010455:Peptides; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C086973:rpr protein, Drosophila; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2