Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction

The Journal of Biological Chemistry
Ramesh HegdeEmad S Alnemri

Abstract

To identify human proteins that bind to the Smac and caspase-9 binding pocket on the baculoviral inhibitor of apoptosis protein (IAP) repeat 3 (BIR3) domain of human XIAP, we used BIR3 as an affinity reagent, followed by elution with the BIR3 binding peptide AVPIA, microsequencing, and mass spectrometry. The mature serine protease Omi (also known as HtrA2) was identified as a mitochondrial direct BIR3-binding protein and a caspase activator. Like mature Smac (also known as Diablo), mature Omi contains a conserved IAP-binding motif (AVPS) at its N terminus, which is exposed after processing of its N-terminal mitochondrial targeting sequence upon import into the mitochondria. Mature Omi is released together with mature Smac from the mitochondria into the cytosol upon disruption of the outer mitochondrial membrane during apoptosis. Finally, mature Omi can induce apoptosis in human cells in a caspase-independent manner through its protease activity and in a caspase-dependent manner via its ability to disrupt caspase-IAP interaction. Our results provide clear evidence for the involvement of a mitochondrial serine protease in the apoptotic pathway, emphasizing the critical role of the mitochondria in cell death.

References

Jan 1, 1974·Methods in Enzymology·J W Greenawalt
Jul 17, 1997·Nature·Q L DeverauxJ C Reed
Apr 29, 1998·Cell Biology and Toxicology·E SolaryM Haugg
Feb 17, 1999·Genes & Development·Q L Deveraux, J C Reed
Jul 17, 1999·Trends in Cell Biology·L K Miller
Oct 8, 1999·Trends in Cell Biology·J M Abrams
May 10, 2000·Nature Medicine·G Kroemer, J C Reed
Aug 22, 2000·The Journal of Biological Chemistry·S M SrinivasulaE S Alnemri
Sep 20, 2000·Leukemia·D E Johnson
Feb 13, 2001·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·K F Ferri, G Kroemer

❮ Previous
Next ❯

Citations

Nov 13, 2008·Apoptosis : an International Journal on Programmed Cell Death·Jung Hwa OhTaeg Kyu Kwon
May 30, 2009·Apoptosis : an International Journal on Programmed Cell Death·Ronald J Krieser, Kristin White
Jun 23, 2011·Apoptosis : an International Journal on Programmed Cell Death·Bavat BornsteinSarit Larisch
Aug 4, 2007·Pharmaceutical Research·Marcello D'AmelioFrancesco Cecconi
Jun 1, 2005·Biochemical and Biophysical Research Communications·Ryungsa Kim
Oct 31, 2003·Biochimie·Frédéric PetitJérôme Estaquier
Dec 4, 2003·Current Opinion in Cell Biology·Andreas BergmannMayank Srivastava
Apr 28, 2004·Cytokine & Growth Factor Reviews·Dhananjaya V Kalvakolanu
Oct 19, 2004·FEMS Yeast Research·Wilfried Bursch
Oct 8, 2013·Protein Expression and Purification·Rukkit SuwannaboonTriwit Rattanarojpong
Jun 22, 2005·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Donato GoffredoElena Cattaneo
May 6, 2003·Biochemical and Biophysical Research Communications·José C Fernández-Checa
May 6, 2003·Biochemical and Biophysical Research Communications·Maria van GurpPeter Vandenabeele
May 6, 2003·Biochemical and Biophysical Research Communications·David L Vaux, John Silke
Oct 14, 2003·Biochemical Pharmacology·Catherine Stenson-CoxAfshin Samali
Dec 21, 2002·Molecular Immunology·Christoph Borner
Feb 11, 2003·Pharmacology & Therapeutics·Angela ClerkDonna M Valks
Dec 4, 2001·Trends in Pharmacological Sciences·M MacFarlane
Mar 27, 2003·Progress in Neuro-psychopharmacology & Biological Psychiatry·Andréa C LeBlanc
May 23, 2002·Biochimie·Kelvin CainGerald M Cohen
Jan 31, 2002·Current Biology : CB·Srinivasa M SrinivasulaEmad S Alnemri
Feb 5, 2003·Drug Discovery Today·Marek LosAndrzej Mackiewicz
Jun 6, 2003·Mutation Research·Simone HuettenbrennerGeorg Krupitza
Feb 9, 2008·Cell Death and Differentiation·F S KhanE S Alnemri
Feb 9, 2008·Cell Death and Differentiation·M MarabeseM Broggini
Oct 1, 2011·Cell Death and Differentiation·T KaufmannP J Jost
Sep 7, 2013·Cell Death & Disease·T K Oberoi-KhanujaK Rajalingam
Nov 3, 2007·Nature Cell Biology·Emad S Alnemri
Nov 3, 2004·Nature Reviews. Molecular Cell Biology·Stefan J Riedl, Yigong Shi
Apr 2, 2005·Nature Reviews. Molecular Cell Biology·David L Vaux, John Silke
Aug 24, 2004·Nature Reviews. Neuroscience·Susanna C Benn, Clifford J Woolf
Oct 22, 2008·Oncogene·E C LaCasseR G Korneluk
Jan 5, 2008·Cell Death and Differentiation·L Vande WalleP Vandenabeele
Sep 10, 2004·Leukemia·O Micheau, D Mérino
Nov 19, 2003·European Journal of Biochemistry·Lidia SemenkovaTimo Korpela

❮ Previous
Next ❯

Related Concepts

Related Feeds

Apoptotic Caspases

Apoptotic caspases belong to the protease enzyme family and are known to play an essential role in inflammation and programmed cell death. Here is the latest research.

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis