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

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 3 in 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.

Pubmed ID: 11604410


  • 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


The Journal of biological chemistry

Publication Data

January 4, 2002

Associated Grants


Mesh Terms

  • Amino Acid Sequence
  • Apoptosis
  • Binding Sites
  • Caspase 3
  • Caspase Inhibitors
  • Chromosomal Proteins, Non-Histone
  • Cytosol
  • Humans
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins
  • Mitochondria
  • Mitochondrial Proteins
  • Molecular Sequence Data
  • Neoplasm Proteins
  • Proteins
  • Serine Endopeptidases
  • Ultraviolet Rays
  • X-Linked Inhibitor of Apoptosis Protein