HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins

Verhagen, AM; Silke, J; Ekert, PG; Pakusch, M; Kaufmann, H; Connolly, LM; Day, CL; Tikoo, A; Burke, R; Wrobel, C; Moritz, RL; Simpson, RJ; Vaux, DL

Author(s): Verhagen, AM; Silke, J; Ekert, PG; Pakusch, M; Kaufmann, H; Connolly, LM; Day, CL; Tikoo, A; Burke, R; Wrobel, C; Moritz, RL; Simpson, RJ; Vaux, DL;
Details: Publication Year 2002-01-04,Volume 277,Issue #1,Page 445-454
Journal Title: JOURNAL OF BIOLOGICAL CHEMISTRY
Publication Type: Journal Article
Abstract: 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 DLABLO/Smac, prevent XIAP inhibition of active caspase 3 in vitro and is able to counteract XIAP protection of mammalian NT2 cells against UV-indueed 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 LAP 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.
Publisher: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Keywords: DROSOPHILA CASPASE DRONC; STRUCTURAL BASIS; IAP; SMAC/DIABLO; GENE; SURVIVAL; SEQUENCE; BINDING; FAMILY; DIAP1
Publisher's Version: https://doi.org/10.1074/jbc.M109891200
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2002-01-04 12:00:00