Identification of Omi/HtrA2 as a Mitochondrial Apoptotic Serine Protease That Disrupts Inhibitor of Apoptosis Protein-Caspase Interaction*

By R. Hegde, S. Srinivasula, Zhijia Zhang, R. Wassell, Rula Mukattash, L. Cilenti, G. Dubois, Y. Lazebnik, A. Zervos, T. Fernandes-Alnemri and 1 more. Journal of Biological Chemistry, 2002

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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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e806d85d49e988ee33f5e36bffd2a984449cda39

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Citations in the corpus

Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012 (2011, background): “In addition, HTRA2 exerts caspase-independent pro-apoptotic effects by virtue of its serine protease activity.(75,76) These mechanisms”
Mitochondrial dysfunction: mechanisms and advances in therapy (2024, background): “172 173 – 175 The binding of cytochrome c with apoptotic peptidase activating factor 1 (APAF1) engenders the assembly of a pivotal multi-protein complex known as the apoptosome, heralding the initiation of the apoptotic cascade.”
Cytochrome c: functions beyond respiration (2008, background): “OMI/HTRA2 is a Ser protease that degrades important structural and regulatory components of the cell in a caspase-independent manne”
Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies (2016, background): “Other apoptotic factors that are released from the mitochondrial intermembrane space into the cytoplasm include apoptosis inducing factor (AIF), second mitochondria-derived activator of caspase (Smac), direct IAP Binding protein with Low pI (DIABLO) and Omi/high temperature requirement protein A (Ht”
The role of mitochondria in apoptosis. (2008, background): “Bax and Bak induce cell death via MOMP that leads to the release of small pro-apoptotic molecules such as cytochrome c (25), second mitochondria-derived activator of caspase/direct IAP (inhibitor-of apoptosis) binding protein with low pI (Smac/Diablo) (26), Omi/HtrA2 (27), apoptosis-inducing factor ”