HtrA2 Promotes Cell Death through Its Serine Protease Activity and Its Ability to Antagonize Inhibitor of Apoptosis Proteins*
By A. Verhagen, J. Silke, P. Ekert, M. Pakusch, H. Kaufmann, L. Connolly, C. Day, A. Tikoo, R. Burke, Carolyn Wrobel and 3 more. Journal of Biological Chemistry, 2002
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Inhibitor of apoptosis (IAP) proteins inhibit caspases, a function counteracted by IAP antagonists, insect Grim, HID, and Reaper and mammalian DIABLO/Smac. We now demonstrate that HtrA2, a mammalian homologue of the Escherichia coli heat shock-inducible protein HtrA, can bind to MIHA/XIAP, MIHB, and baculoviral OpIAP but not survivin. Although produced as a 50-kDa protein, HtrA2 is processed to yield an active serine protease with an N terminus similar to that of Grim, Reaper, HID, and DIABLO/Smac that mediates its interaction with XIAP. HtrA2 is largely membrane-associated in healthy cells, with a significant proportion observed within the mitochondria, but in response to UV irradiation, HtrA2 shifts into the cytosol, where it can interact with IAPs. HtrA2 can, like DIABLO/Smac, prevent XIAP inhibition of active caspase 3in vitro and is able to counteract XIAP protection of mammalian NT2 cells against UV-induced cell death. The proapoptotic activity of HtrA2 in vivo involves both IAP binding and serine protease activity. Mutations of either the N-terminal alanine of mature HtrA2 essential for IAP interaction or the catalytic serine residue reduces the ability of HtrA2 to promote cell death, whereas a complete loss in proapoptotic activity is observed when both sites are mutated.
Subfields: Complementary and alternative medicine, Neurology, Plant Science
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Citations in the corpus
- 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.”
- The Bcl-2 family: roles in cell survival and oncogenesis (2003, background): “…al., 1996); Smac/Diablo and Omi/HtrA2, which antagonize the ability of lAPs (Inhibitors of Apoptosis Proteins) to inhibit caspases (Du et al., 2000; Verhagen et al., 2000, 2002; Suzuki et al., 2001); endonuclease G, which may aid CAD (caspase-activated DNAse) in DNA fragmentation (Li et al., 2001;…”
- Role of Bcl-2 family proteins and caspases in the regulation of apoptosis (2011, background): “It prevents the IAP’s action via amino-terminal reaper-related motif which induces caspase activity [99, 146–148].”
- Toxic proteins released from mitochondria in cell death (2004, background): “Mutational analysis revealed that the binding of HtrA2/OMI to BIR3 is enhanced by changing A147 (the fourth amino-acid residue in the IBM of mouse HtrA2/ Oncogene OMI) into Ile, as present in DIABLO (Verhagen et al., 2002).”
- The role of mitochondrial factors in apoptosis: a Russian roulette with more than one bullet (2002, background): “Omi/HtrA2 interacts with both the BIR2 and BIR3 domains of XIAP, although with higher affinity for the BIR2, as opposed to Smac/DIABLO, which preferentially binds the BIR3 domain.(17,20) This selectivity suggests that Omi/HtrA2 may promote preferentially caspase-3 activation rather than caspase-9 ac”