HTRA2

HTRA2 Background

The HTRA2 protein, also called Omi, is a serine protease encoded by the HTRA2 gene ^[1][2]. It belongs to the HtrA family of evolutionarily conserved ATP-independent serine proteases, homologs of the HtrA (DegP) serine protease from the bacterium Escherichia coli. HTRA2/Omi is expressed as a 49-kDa proenzyme targeted to the mitochondrial intermembrane space (IMS), where it undergoes proteolytic maturation via cleavage of the first 133 N-terminal residues ^[3]. The full-length HtrA2 contains the N-terminal mitochondrial targeting sequence, a transmembrane domain, followed by a serine protease domain with the catalytic triad His198-Asp228-Ser306, and a C-terminal PDZ domain. The mature HTRA2/Omi was identified as a mitochondrial direct BIR3-binding protein and a caspase activator ^[4]. Like mature Smac (also known as DIABLO), mature HTRA2/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 ^[4]. During apoptosis, mature HTRA2/Omi is released together with mature Smac/DIABLO from the mitochondria into the cytosol upon disruption of the outer mitochondrial membrane during apoptosis ^[4][6]. Finally, mature HTRA2/Omi induces 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 (inhibitor of apoptosis protein) interaction through its Reaper-like motif ^[4][5][6]. Ser306 is the active site of the protease domain, and mutation of Ser306 inactivates HTRA2/Omi ^[7]. Ser142 and Ser400 are the known phosphorylation sites of HtrA2/Omi ^[8][9]. Upon oxidative stress, p38 MAPK phosphorylates Ser142 of HTRA2/Omi in a PINK1-dependent manner ^[10]. CDK5 phosphorylates Ser400 of HTRA2/Omi in a p38-dependent manner, resulting in the enhancement of HTRA2/Omi proteolytic activity and increased resistance of cells to mitochondrial stress. HTRA2/Omi has, therefore, been proposed to be a pro-apoptotic protein. Additionally, HTRA2/Omi is required for maintaining mitochondrial function ^[7]. Under normal physiological conditions, HTRA2/Omi acts as a quality control factor and promotes cell survival. Disturbances of the HTRA2/Omi proteolytic activity lead to the accumulation of unfolded proteins in mitochondria, dysfunction of the mitochondrial respiration, generation of reactive oxygen species, and result in a loss of mitochondrial competence. A recent study demonstrated the phosphorylation of HTRA2/Omi at a residue adjacent to a position found mutated in patients with Parkinson's disease ^[8][11]. Analysis of available microarray data indicated that the expression of HTRA2 in different cancers varies according to tumor type ^[12].

[1] Gray CW, Ward RV, et al. Characterization of human HtrA2, a novel serine protease involved in the mammalian cellular stress response [J]. European Journal of Biochemistry / FEBS. 2000, 267 (18): 5699-710.
[2] Faccio L, Fusco C, et al. Characterization of a novel human serine protease that has extensive homology to bacterial heat shock endoprotease HtrA and is regulated by kidney ischemia [J]. The Journal of Biological Chemistry. 2000, 275 (4): 2581-8.
[3] Faccio L, Fusco C, et al. Characterization of a novel human serine protease that has extensive homology to bacterial heat shock endoprotease HtrA and is regulated by kidney ischemia [J]. J Biol Chem. 2000 Jan 28; 275(4):2581-8.
[4] Hegde R, Srinivasula SM, et al. Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction [J]. J Biol Chem 2002; 277: 432-438.
[5] Martins LM, Iaccarino I, et al. The serine protease Omi/HtrA2 regulates apoptosis by binding XIAP through a reaper-like motif [J]. J Biol Chem 2002; 277: 439-444.
[6] Suzuki Y, Imai Y, et al. A serine protease, HtrA2, is released from the mitochondria and interacts with XIAP, inducing cell death [J]. Mol Cell. 2001 Sep; 8(3):613-21.
[7] Jones JM, Datta P, et al. Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice [J]. Nature. 2003 Oct 16; 425(6959):721-7.
[8] lun-Favreau H, Klupsch K, et al. The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1 [J]. Nat Cell Biol. 2007 Nov; 9(11):1243-52.
[9] Fitzgerald JC, Camprubi MD, et al. Phosphorylation of HtrA2 by cyclin-dependent kinase-5 is important for mitochondrial function [J].
Cell Death Differ. 2012 Feb; 19(2):257-66.
[10] Plun-Favreau H, Klupsch K, et al. The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1 [J]. Nat Cell Biol. 2007 Nov; 9(11):1243-52.
[11] Strauss KM, Martins LM, et al. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease [J]. Hum Mol Genet 2005; 14: 2099-2111.
[12] Jeremy Chien, Mara Campioni, et al. HtrA Serine Proteases as Potential Therapeutic Targets in Cancer [J]. Curr Cancer Drug Targets. 2009 Jun; 9(4): 451-468.