The Serine Protease Omi/HtrA2 Regulates Apoptosis by Binding XIAP through a Reaper-like Motif*

By L. M. Martins, I. Iaccarino, T. Tenev, S. Gschmeissner, N. Totty, N. Lemoine, J. Savopoulos, C. Gray, C. Creasy, C. Dingwall and 1 more. Journal of Biological Chemistry, 2002

601 citations recorded by the source corpus.

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.

Subfields: Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/092e1238b19599cf30fbf20ba6a741f5736e7bee

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In Epidemiology

1. Simone Fulda
2. K. Debatin
3. H. Plun-Favreau
4. Peter Vandenabeele

In Molecular Biology

1. Simone Fulda
2. K. Debatin
3. Peter Vandenabeele
4. G. van Loo
5. X. Saelens
6. Maria van Gurp
7. Fenghe Du
8. T. Kuwana

Citations in the corpus

• Positional effects of short interfering RNAs targeting the human coagulation trigger Tissue Factor. (2002, background): “Very recently, siRNA was also used to knock down expression of HtrA2 (28).”
• Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. (2005, background): “We confirmed the previously reported predominant mitochondrial localization of Omi/HtrA2 protein in cells as assessed by immunofluorescence (4,6) (Fig.”
• Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy (2006, background): “Decreasing the levels of HtrA2/OMI in cells by antisense or RNA interference lowers the sensitivity of different cancer cell lines to cell death induced by staurosporin, Fas, UV or cisplatin (Martins et al., 2002).”
• Bcl-2-family proteins and the role of mitochondria in apoptosis. (2003, background): “The contribution of the intrinsic pathway in such cases could be mediated by any of several IMS proteins, including cytochrome c, Smac/DIABLO [20,21], Omi/Htra2 [22–24], endonuclease G [25] and apoptosis-inducing factor (AIF) [26,27].”
• Toxic proteins released from mitochondria in cell death (2004, background): “Processing of this second leader, which occurs in a subpopulation of the HtrA2/ OMI pool, exposes an IBM and generates mature 35 kDa HtrA2/OMI (Suzuki et al., 2001a; Hegde et al., 2002; Martins et al., 2002; van Loo et al., 2002b; Verhagen et al., 2002).”