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FLASH GENE
Symbol HTRA2 contributors: mct/npt/pgu - updated : 13-06-2019
HGNC name HtrA serine peptidase 2
HGNC id 14348
Corresponding disease
MGCA8 3-methylglutaconic aciduria, type VIII
PARK13 Parkinson disease 13
Location 2p13.1      Physical location : 74.756.531 - 74.760.683
Synonym name
  • protease, serine, 25
  • high temperature requirement protein A2
  • Omi stress-regulated endoprotease
  • serine protease HTRA2, mitochondrial
    • Synonym symbol(s) HTRA, OMI, PRSS25, PARK13, MGCA8
    EC.number 3.4.21.108
    DNA
    TYPE like-sequence
    SPECIAL FEATURE overlapping, gene in gene
    text LOXL3
    STRUCTURE 4.15 kb     8 Exon(s)
    MAPPING cloned Y linked N status provisional
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    8 splicing 2550 48.8 458 ubiquitous 2008 18060880
    6 splicing 2259 - 361 predominantly in the kidney, colon and thyroid 2008 18060880
  • lacking exons 3 and 7
  • having a modified PDZ domain
  • having no detectable protease activity
    • 7 - 2484 - 436 - 2008 18060880
    7 - 2454 - 426 - 2008 18060880
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart    
    Digestivesalivary gland   highly
    Endocrinepancreas    
    Nervousbrain    
    Reproductivefemale systemuteruscervix highly
    Urinarykidney    
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularstriatumskeletal  
    cell lineage
    cell lines promyelocytic leukemia, chronic myelogenous leukemia, Burkitt lymphoma, and colorectal carcinoma lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a PDZ/DHR domain, a serine protease domain and a postsynaptic density of 95 kDa, disk large, and zonula occludens 1 (PDZ) regulatory domain and functions both as a protease and a chaperone
  • a Src homology 3-binding domain
    • mono polymer homomer , trimer
    isoforms Precursor
    HOMOLOGY
    interspecies homolog to murine Htra2
    intraspecies homolog to HTRA1
    Homologene
    FAMILY
  • peptidase family S2C
  • HtrA family
    • CATEGORY chaperone/stress , enzyme , regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria,interspace
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,cytosolic
    intracellular,cytoplasm,cytoskeleton
    intracellular,nucleus,chromatin/chromosome
    text localized to the mitochondria with release to the cytosol following apoptotic stimulus
    basic FUNCTION
  • promoting cytochrome c (Cyt c)dependent caspase activation
  • inducing apoptosis by binding the apoptosis inhibitory protein baculoviral IAP repeat-containing 4 (BIRC)
  • serine-type endopeptidase involved in stress response pathways
  • is released from mitochondria and inhibits the function of XIAP
  • is a SMAC-like inhibitor of IAP (inhibitor of apoptosis proteins) activity
  • could have protective functions in mitochondria
  • a proapoptotic molecule that proteolyses several proteins to induce cell death
  • its protease activity is involved not only in apoptosis but also in cellular homeostasis
  • inhibits mitochondrial superoxide generation, stabilizes mitochondrial membrane potential, and prevents apoptosis at baseline and in response to extracellular inducers of mitochondrial stress
  • novel regulator of autophagy and suggesting that HTRA2 might be important in the cellular quality control of proteins involved in neurodegenerative diseases
  • HTRA2-mediated cleavage of UCHL1 may play important roles in regulating the fine balance between cell growth and cell death
  • UCHL1 and HTRA2 pair may play important roles in regulating the balance between cell death and cell survival
  • normally exists in the mitochondria, can cause MMP3 activation in the cytosol under a cell stress condition, which can ultimately lead to demise of dopaminergic neuronal cells
  • involved in the maintenance of mitochondrial homeostasis and in the stimulation of apoptosis, as well as in cancer and neurodegenerative disorders
  • intrinsic cellular factor that inhibits neuroinflammation
  • ATP-independent serine protease located in the intermembrane space of the mitochondria that is thought to function as a protein quality control protease
  • its activity in neuronal mitochondria is important for neuronal cell survival
  • HTRA2-regulated protein quality control in the intermembrane space of mitochondria is important for the maintenance of mitochondrial homeostasis, and loss of HTRA2 activity can lead to both neurodegeneration and aging
  • PARL protein and HTRA2 are key regulators of mitochondrial integrity and play pivotal roles in apoptosis
  • MUL1 E3 ubiquitin ligase is a specific substrate of HTRA2
  • is a novel regulator of mitochondrial biogenesis, involving in HTRA2 protease-deficient-induced neurodegeneration
  • HTRA2 is likely essential for maintenance of the mitochondrial integrity in neurons
  • HTRA1, HTRA2, HTRA3, HTRA4 function as important modulators of many physiological processes, including maintenance of mitochondrial homeostasis, cell signaling and apoptosis
  • is a mitochondrial serine protease involved in several cellular processes, including autophagy, chaperone activity, and apoptosis
  • promotes apoptosis through either the caspase-dependent or caspase-independent pathway
  • is a proapoptotic mitochondrial serine protease involved in caspase-dependent cell apoptosis, translocating from mitochondria to the cytosol after an apoptotic insult
  • importance of HTRA2 in regulating colitis by modulation of necroptosis
    • CELLULAR PROCESS cell life, cell death/apoptosis
    protein, degradation
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • formation of a pyramid-shaped homotrimer mediated exclusively by the serine protease domains
    • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • binding to an alternatively spliced form of mitogen-activated protein kinase 14
  • binding to p38 stress-activated kinase MXI2
  • binding to the apoptosis inhibitory proteins baculoviral IAP repeat-containing 4 (BIRC), BIRC2, BIRC3 and XIAP
  • interacts with LATS1 through the protein/discs-large protein/zonula (PDZ) domain
  • interacting with MPV17L
  • interacting with THAP5 (THAP5 is cleaved and removed by the proapoptotic HTRA2 protease)(
  • is a WT1 binding partner that cleaves WT1 at multiple sites following the treatment of cells with cytotoxic drugs
  • ITGA7 increases the protease activity of HTRA2, and deletion of the HTRA2 interaction domain abrogates the cell death activity of ITGA7, whereas down-regulation of HTRA2 dramatically reduced cell death mediated by ITGA7
  • PSEN1, as previously reported to activate HTRA2, interacts with HTRA2 in isolated mitochondria
  • UCHL1 is a natural substrate for the serine protease HTRA2 in the apoptotic pathway
  • platelets have a functional intrinsic apoptotic-signalling pathway including the pro-apoptotic protease HTRA2 and its target protein XIAP
  • AREL1 interacted with and ubiquitinated IAP antagonists such as DIABLO, HTRA2, and ARTS
  • downregulation of PARL after ischemia is a key step in ischemic neuronal injury, and it decreases HTRA2 processing and increases neuronal vulnerability
  • MUL1 E3 ubiquitin ligase is a specific substrate of HTRA2, and inactivation of HTRA2 protease leads to the deregulation of mitochondrial MUL1 E3 ubiquitin ligase and increased mitophagy
  • CSPG4 binds HTRA2, a mitochondrial serine protease which is released from damaged mitochondria into the cytosol in response to stress, and may thus help protect cells against oxidative stress-induced cell death
  • induced mitochondrial pathway apoptosis, which involves inhibition of an important antiapoptotic protein XIAP and influence on MMP
  • HTRA2 directly interacted with RIPK1 and promoted its degradation during a specific time phase of necroptosis
    • cell & other
    REGULATION
    activated by presenilin 1 through direct interaction with the PDZ domain
    Phosphorylated by CDK5 (phosphorylation at S400 is involved in maintaining mitochondrial membrane potential under stress conditions and is important for mitochondrial function, conferring cells protection against cellular stress)
    Other upregulated in response to stress induced by heat shock and tunicamycin treatment
    undergoing autoproteolysis, crucial for regulating HTRA2-mediated apoptotic cell death
    ASSOCIATED DISORDERS
    corresponding disease(s) PARK13 , MGCA8
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --low  
    may contribute to the potent anti-atherosclerotic effect of shear stress by preventing endothelial cells from entering apoptosis
    Susceptibility
  • to Parkinson disease (not PARK3)
  • ton Alzheimer disease (AD)
    • Variant & Polymorphism other
  • mutation G399S and A141S increasing the risk of Parkinson disease (mutation associated with altered mitochondrial morphology)
  • a weak association of A141S with AD
    • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    immunologyinflammatory 
    is an attractive target for anti-colitis treatment
    ANIMAL & CELL MODELS
  • neurodegeneration and juvenile lethality in mnd2 (motor neuron degeneration-2) mice result from the missense mutation ser276 to cys (S276C) in the protease domain of the nuclear-encoded mitochondrial serine protease Omi
  • mice lacking Omi/HtrA2 exhibited progeria symptoms (premature aging)