Disease relevance of Htra2

• The genes are located approximately 2 cM distal to mnd2, a mouse mutation causing neuromuscular disease [1].
• Omi release also occurs in apoptotic dying but not in necrotic dying fibrosarcoma L929 cells, treated with anti-Fas antibodies and TNF, respectively [2].
• Human HtrA2 is a novel member of the HtrA serine protease family and shows extensive homology to the Escherichia coli HtrA genes that are essential for bacterial survival at high temperatures [3].
• The proteolytic activity of Omi is markedly up-regulated in the mouse kidney following ischemia/reperfusion [4].
• The mouse mutant "motoneuron disease 2" (MND2, mnd2 on Chr 6) was originally characterized as a spinal muscular atrophy (SMA) because degenerating motoneurons were observed in late stages of the disease [5].

High impact information on Htra2

• This suggests that instead of promoting cell death by antagonizing inhibitor of apoptosis (IAP) proteins, the primary function of HtrA2/Omi is to handle misfolded proteins in the mitochondria [6].
• Recently targeted disruption of Omi/HtrA2 has been found to cause neurodegeneration and a parkinsonian phenotype in mice [7].
• Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease [7].
• The serine proteases were found to act upstream of an increase in mitochondrial membrane permeability as opposed to the serine protease Omi/HtrA2 which is released from mitochondria at a later stage [8].
• Proteome analysis of supernatant of isolated mitochondria exposed to recombinant tBid, a proapoptotic Bcl-2 member, revealed the presence of the serine protease Omi, also called HtrA2 [2].

Chemical compound and disease context of Htra2

• A specific inhibitor of Omi/HtrA2, a serine protease implicated in cisplatin-induced apoptosis, prevented renal failure and increased survival [9].

Biological context of Htra2

• We report here the phenotype of mice entirely lacking expression of HtrA2/Omi due to targeted deletion of its gene, Prss25 [10].
• High-resolution genetic, physical, and transcript map of the mnd2 region of mouse chromosome 6 [11].
• The amino acid sequence reveals the presence of an XIAP interaction motif at the N-terminus of mature Omi [2].
• Oncogenic Ras inhibits anoikis of intestinal epithelial cells by preventing the release of a mitochondrial pro-apoptotic protein Omi/HtrA2 into the cytoplasm [12].
• Instead, anoikis of intestinal epithelial cells is triggered by the release of a mitochondrial protein Omi/HtrA2, an event driven by detachment-induced down-regulation of Bcl-X(L) [12].

Anatomical context of Htra2

• mnd2: a new mouse model of inherited motor neuron disease [13].
• The HtrA2-cleaved C161 fragment was detected in the cytosolic fraction; therefore, we postulate that the C161 fragment is released into the cytosol after cleavage of APP by HtrA2 [14].
• Loss of Omi protease activity increases the susceptibility of mitochondria to induction of the permeability transition, and increases the sensitivity of mouse embryonic fibroblasts to stress-induced cell death [15].
• Cleavage of HAX-1 was not observed in a cell line derived from motor neuron degeneration 2 mice that carry a mutated form of Omi that affects its proteolytic activity [16].
• Studies in mice gene-deleted for Omi/HtrA2 and AIF showed the involvement of these mitochondrial proteins in selective cell degeneration in the spinal cord and brain [17].

Associations of Htra2 with chemical compounds

• In this report, we investigated the role of Omi in renal cell death following cisplatin treatment [18].
• Location of thiamine pyrophosphatase activity as a marker of the Golgi apparatus was studied ultracytochemically in mouse oocytes with germinal vesicle (OGV), oocytes at metaphase I (OMI) and oocytes at metaphase II (OMII), and further in cells of the respective cumulus oophorus serving as comparative objects [19].
• Abolishing HtrA2/Omi phosphorylation by Akt through mutation of serine 212 to alanine (HtrA2/Omi-S212A) retains its serine protease activity and induces more apoptosis as compared with wild-type HtrA2/Omi [20].

Other interactions of Htra2

• The results localize mnd2 to the 0.2-cM interval between D6Mit164 and D6Mit128 [11].
• Mouse p150Glued (dynactin 1) cDNA sequence and evaluation as a candidate for the neuromuscular disease mutation mnd2 [21].
• Release of Omi under apoptotic conditions was confirmed in vivo in livers from mice injected with agonistic anti-Fas antibodies and was prevented in livers from Bcl-2 transgenic mice [2].
• The human HtrA family of proteases consists of four members: HtrA1, HtrA2, HtrA3, and HtrA4 [22].
• Analysis of a cross segregating the neurological mutant mnd2 excluded Taut as a candidate gene for this closely linked mutation [23].

Analytical, diagnostic and therapeutic context of Htra2

• Northern blot analysis, complete sequencing of the cDNA, Western blot, and functional tests of the protein did not detect any abnormalities of p150Glued in mnd2 mice [21].
• Immunohistochemistry and functional analysis in stably transfected cells revealed that S399 mutant Omi/HtrA2 and to a lesser extent, the risk allele of the A141S polymorphism induced mitochondrial dysfunction associated with altered mitochondrial morphology [7].
• Using primary mouse proximal tubule cells, as well as established renal cell lines, we show that the level of Omi protein is upregulated after treatment with cisplatin [18].

References