Affinage

HTRA1

Serine protease HTRA1 · UniProt Q92743

Length
480 aa
Mass
51.3 kDa
Annotated
2026-04-28
100 papers in source corpus 27 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HTRA1 is a secreted homotrimeric serine protease that functions as a broad-spectrum extracellular matrix remodeler, protein aggregate disaggregase, and signaling pathway modulator in vascular, neural, ocular, and skeletal tissues. The enzyme assembles as a trimer whose trypsin-like catalytic domain adopts a constitutively competent conformation, with substrate engagement further regulated by allosteric activation through its C-terminal PDZ domain upon binding hydrophobic peptide sequences (PMID:17962403, PMID:22578544). HTRA1 degrades diverse ECM substrates (fibronectin, decorin, MGP, LTBP-1, EFEMP1, TSP1, OPG, EGFL8) and amyloid fibrils (tau, α-synuclein), with its fibril-disaggregase activity being ATP-independent and, for α-synuclein, proteolysis-independent (PMID:26436840, PMID:38499535, PMID:16377621, PMID:30854478); it represses TGF-β/BMP signaling, inhibits canonical Wnt/β-catenin signaling, and promotes Notch signaling by cleaving JAG1 (PMID:19387015, PMID:29269789, PMID:29713059). Loss-of-function mutations cause CARASIL and dominant CADASIL-like cerebral small vessel disease through impaired protease activity and, in heterozygous cases, dominant-negative disruption of the trimeric complex (PMID:19387015, PMID:27164673, PMID:34626176).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2005 High

    Establishing HTRA1 as an ECM-degrading and APP-processing extracellular protease resolved the question of what substrates this secreted serine protease acts on, revealing roles in both matrix turnover and amyloid clearance.

    Evidence In vitro cleavage assays with fibronectin and APP fragments, mass spectrometry of synovial fluid substrates, cell culture inhibitor experiments, and downstream MMP induction readouts

    PMID:15855271 PMID:16377621

    Open questions at the time
    • Full substrate repertoire in vivo undefined
    • Cleavage site specificity rules not determined
    • In vivo relevance of APP degradation not established
  2. 2006 High

    Linking the HTRA1 promoter variant rs11200638 to AMD and detecting HTRA1 in drusen provided the first evidence that elevated HTRA1 protease activity contributes to retinal disease, while showing that HTRA1 upregulation promotes chemotherapy-induced cell death established a pro-apoptotic role for the active protease.

    Evidence SNP genotyping with expression analysis in patient lymphocytes/RPE and drusen immunolabeling; forced expression/knockdown in ovarian cancer cells with protease-dead controls

    PMID:16767218 PMID:17053109

    Open questions at the time
    • Causal mechanism linking HTRA1 overexpression to drusen formation not defined
    • Apoptotic substrate(s) mediating cell death not identified
  3. 2007 High

    Structural and biochemical dissection of the PDZ domain revealed an allosteric activation mechanism whereby hydrophobic peptide binding to the PDZ domain induces conformational changes that activate the protease, and showed that substrate-specific cleavage (e.g., MGP) can require both the PDZ and protease domains.

    Evidence Crystal structures of PDZ–ligand complexes, peptide library screening, alanine scanning mutagenesis, domain-deletion cleavage assays with decorin/fibronectin/MGP

    PMID:17962403 PMID:18156628

    Open questions at the time
    • Full-length trimer structure with PDZ-protease allosteric interface not resolved
    • Which in vivo substrates require PDZ-dependent activation unknown
  4. 2009 High

    Identifying loss-of-function HTRA1 mutations as the genetic cause of CARASIL, with mutant proteins showing defective protease activity and failure to repress TGF-β signaling, established HTRA1 as a non-redundant vascular protease and TGF-β pathway repressor.

    Evidence Linkage analysis across five families, sequencing, casein protease assays, TGF-β signaling assays, immunohistochemistry of patient cerebral arteries

    PMID:19387015

    Open questions at the time
    • Molecular mechanism of TGF-β repression (direct substrate vs indirect) not resolved
    • Whether other HtrA family members compensate partially unknown
  5. 2011 High

    Transgenic HTRA1 overexpression in mouse RPE was sufficient to cause polypoidal choroidal vasculopathy and choroidal neovascularization with VEGF upregulation, providing causal in vivo evidence that excess HTRA1 drives AMD-related vascular pathology.

    Evidence Transgenic mouse model with RPE-directed human HTRA1 expression, fundus imaging, histology, VEGF measurement

    PMID:21844367

    Open questions at the time
    • Which HTRA1 substrates mediate the choroidal vascular phenotype not identified
    • Relationship between ECM degradation and VEGF induction not mechanistically defined
  6. 2012 High

    Demonstrating that HTRA1 degrades tau aggregates and fibrils, combined with crystal structures revealing a constitutively competent trimeric protease domain, established HTRA1 as an ATP-independent protein disaggregase and clarified the structural basis of its active-site accessibility.

    Evidence In vitro tau fibril degradation, neuronal cell overexpression, patient brain immunohistochemistry; X-ray crystallography and SAXS of full-length HTRA1 trimer

    PMID:22535953 PMID:22578544

    Open questions at the time
    • How the trimer engages fibrillar vs. soluble substrates structurally not resolved
    • In vivo contribution to tauopathy clearance not tested in animal models
  7. 2012 Medium

    Identifying miR-30e and miR-181d as post-transcriptional repressors of HTRA1 via its 3′ UTR, with in vivo rescue of radial glia proliferation defects, revealed a layer of miRNA-mediated HTRA1 regulation relevant to neural progenitor biology.

    Evidence Luciferase reporter assays with HTRA1 3′ UTR, miRNA overexpression in Dicer-KO mouse forebrain, phenotypic rescue

    PMID:22854828

    Open questions at the time
    • Physiological contexts in which miR-30e/miR-181d regulate HTRA1 beyond developing brain not explored
    • Quantitative impact on HTRA1 protein levels in adult tissues unknown
  8. 2013 Medium

    Showing that NF-κB p65 directly binds the HTRA1 promoter upon TLR4/LPS stimulation, and that IFN-γ/STAT1 directly represses HTRA1 transcription, defined the inflammatory transcriptional logic governing HTRA1 expression.

    Evidence ChIP assays, dual-luciferase reporters, NF-κB/STAT1 inhibitors and siRNA, IFN-γ KO mouse model

    PMID:23982886 PMID:24907345

    Open questions at the time
    • Combinatorial regulation by NF-κB and STAT1 under concurrent inflammatory signals not tested
    • Chromatin context and epigenetic modifiers at the HTRA1 locus not comprehensively mapped
  9. 2015 High

    Mechanistic dissection of HTRA1's fibril-disaggregase activity showed ATP-independent solubilization of the fibrillar core, distinguishing HTRA1 from canonical chaperone-disaggregases; structural characterization of an inhibitory antibody-HTRA1 cage complex revealed allosteric inhibition via surface loops B and C.

    Evidence In vitro fibril disaggregation kinetics, cellular tau aggregation models; negative-stain EM of antibody–HTRA1 complex, epitope mapping

    PMID:26385991 PMID:26436840

    Open questions at the time
    • Structural basis of fibril recognition at atomic resolution not determined
    • Whether loops B and C are involved in substrate engagement or purely allosteric sites unclear
  10. 2016 High

    Discovery that heterozygous HTRA1 mutations cause dominant CADASIL-like disease through dominant-negative disruption of the trimer, as distinct from recessive CARASIL mutations that preserve trimer formation, established trimer integrity as a critical determinant of disease mechanism.

    Evidence Casein protease activity assays with WT/mutant co-incubation, gel filtration chromatography for oligomeric state

    PMID:27164673

    Open questions at the time
    • Structural basis for dominant-negative disruption not resolved at atomic level
    • Whether heterozygous carriers have graded substrate-specific deficits unknown
  11. 2018 High

    Identifying JAG1 as an HTRA1 substrate demonstrated that HTRA1 promotes Notch signaling by degrading the Notch ligand JAG1, with loss of HTRA1 causing hypersprouting angiogenesis in vitro and immature tumor vasculature in vivo; HTRA1 sequestration by Notch3ECD in CADASIL vessels linked two cerebral small vessel diseases to a common HTRA1-deficiency mechanism.

    Evidence Co-IP, in vitro cleavage assays, endothelial siRNA/overexpression, HtrA1-KO mouse tumor model with Notch1 rescue; quantitative brain vessel proteomics in CADASIL vs. controls and HtrA1-KO mice

    PMID:29713059 PMID:29725820

    Open questions at the time
    • Whether HTRA1 cleaves JAG1 extracellularly or intracellularly in vivo not definitively resolved
    • Full overlap of HTRA1-dependent proteome between CARASIL and CADASIL not characterized
  12. 2019 High

    Defining HTRA1's role in VSMC differentiation and its cleavage of osteoprotegerin expanded the functional repertoire to include smooth muscle maturation via combined Notch3/TGF-β modulation and bone remodeling through OPG degradation.

    Evidence HtrA1-KO mouse VSMC phenotyping with vasoconstriction assays, JAG1/Notch3/TGF-β pathway Western blots; in vitro OPG cleavage site mapping by mass spectrometry, osteoclastogenesis assays

    PMID:30854478 PMID:31796853

    Open questions at the time
    • Relative contribution of Notch vs. TGF-β arm to VSMC maturation defect not dissected
    • In vivo bone phenotype of HTRA1-KO not reported
  13. 2020 Medium

    Demonstration that RUNX2 and EGR1 co-occupy HTRA1 enhancers to repress transcription during osteoblast differentiation added a developmental transcription factor circuit to the regulatory landscape of HTRA1.

    Evidence ChIP-seq, Re-ChIP, dual-luciferase enhancer assays, siRNA knockdown with osteoblast differentiation readouts

    PMID:32324256

    Open questions at the time
    • Whether RUNX2/EGR1 repression operates in non-skeletal HTRA1-expressing tissues unknown
    • Enhancer–promoter looping mechanism not resolved
  14. 2021 High

    Gene burden analysis linking rare HTRA1 protease-domain variants to white matter hyperintensity volume, with biochemical validation of reduced activity for individual variants and identification of EGFL8 as a novel substrate, extended the genotype–phenotype spectrum beyond Mendelian CARASIL.

    Evidence Whole-exome sequencing burden tests, domain-specific analysis, in vitro protease activity assays for multiple variants, substrate identification

    PMID:34626176

    Open questions at the time
    • Functional role of EGFL8 cleavage in vascular biology not established
    • Threshold of HTRA1 activity loss required for clinical phenotype unknown
  15. 2024 High

    Showing that HTRA1 disaggregates α-synuclein fibrils and inhibits aggregation of α-synuclein, FUS, and TDP-43 through a proteolysis-independent mechanism residing in the protease domain established HTRA1 as a dual-function protein: a protease for soluble substrates and a holdase/disaggregase for amyloid aggregates.

    Evidence In vitro aggregation inhibition and fibril disaggregation with protease-dead mutants and domain deletions, α-syn seeding assays, primary neuron toxicity assays, HTRA1 knockdown

    PMID:38499535

    Open questions at the time
    • Structural basis of the proteolysis-independent disaggregase activity not resolved
    • In vivo relevance to synucleinopathies not tested in animal models
    • Whether holdase and protease activities are coordinated on the same substrate unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • A full-length atomic structure of the HTRA1 trimer including the PDZ–protease allosteric interface, the structural basis of its proteolysis-independent disaggregase activity, and the identity of the critical in vivo substrates whose loss drives cerebral small vessel pathology remain unresolved.
  • No full-length trimeric structure at atomic resolution
  • Proteolysis-independent disaggregase mechanism structurally undefined
  • Causal substrate(s) in cerebral small vessel disease not pinpointed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10 GO:0016787 hydrolase activity 7 GO:0044183 protein folding chaperone 1
Localization
GO:0005576 extracellular region 5 GO:0031012 extracellular matrix 4
Pathway
R-HSA-1643685 Disease 6 R-HSA-1474244 Extracellular matrix organization 4 R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 2
Partners
CTNNB1DCNFN1JAG1MAPTNOTCH3OPGSNCA
Complex memberships
HTRA1 homotrimer

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 A promoter SNP (rs11200638) in HTRA1 is associated with elevated HTRA1 mRNA and protein expression in lymphocytes and retinal pigment epithelium from AMD patients, and HTRA1 protein was found in drusen of AMD patient eyes, implicating increased HTRA1 secreted serine protease activity in AMD pathogenesis. SNP genotyping, expression analysis of patient-derived lymphocytes and RPE, immunolabeling of drusen Science Medium 17053109
2009 Loss-of-function mutations in HTRA1 (nonsense and missense) cause CARASIL; mutant HTRA1 proteins show reduced protease activity and fail to repress TGF-β family signaling, establishing HTRA1 as a repressor of TGF-β signaling in cerebral small vessel homeostasis. Linkage analysis, sequencing, functional protease activity assays (casein), TGF-β signaling assays, immunohistochemistry of patient cerebral arteries New England Journal of Medicine High 19387015
2005 HTRA1 directly degrades fragments of amyloid precursor protein (APP) in vitro, and an HTRA1 inhibitor causes accumulation of Aβ in astrocyte cell culture supernatants; HTRA1 colocalizes with β-amyloid deposits in human brain. In vitro protease assay with APP fragments, cell culture inhibitor experiment, immunohistochemistry of human brain Proceedings of the National Academy of Sciences Medium 15855271
2005 HTRA1 cleaves fibronectin in synovial fluid, generating fibronectin degradation products that induce MMP-1 and MMP-3 expression in synovial fibroblasts, implicating HTRA1 in both direct and indirect ECM destruction in arthritis. Mass spectrometry identification of substrates in synovial fluid, recombinant HTRA1 cleavage assay with fibronectin, fibroblast treatment with HTRA1 or HTRA1-generated fibronectin fragments, MMP expression assay Journal of Biological Chemistry High 16377621
2007 The PDZ domains of human HtrA1 recognize hydrophobic polypeptides (preferring C-terminal sequences but also internal sequences), and peptide binding to the PDZ domain induces conformational changes that activate the protease domain, supporting an allosteric activation mechanism. Peptide library screening, affinity assays, crystal structure of PDZ domain-ligand complexes, alanine scanning mutagenesis Protein Science High 17962403
2007 HTRA1 inhibits osteoblast mineralization in a manner requiring both its protease domain and PDZ domain; it cleaves recombinant decorin, fibronectin, and matrix Gla protein (MGP), with MGP cleavage requiring both domains while decorin/fibronectin cleavage requires only the protease domain. Overexpression and siRNA knockdown in 2T3 osteoblasts, recombinant HTRA1 domain deletion constructs, in vitro cleavage assays of ECM substrates Journal of Biological Chemistry High 18156628
2012 Human HTRA1 degrades aggregated and fibrillar tau in vitro and in cells; HTRA1 mRNA and activity are upregulated in response to elevated tau concentrations, and neuronal cells/patient brains accumulate less tau and neurofibrillary tangles when HTRA1 is expressed at elevated levels. In vitro protease assay with tau aggregates/fibrils, overexpression in neuronal cell lines, immunohistochemistry of patient brains, RT-PCR of HTRA1 mRNA Journal of Biological Chemistry High 22535953
2012 Crystal structures and SAXS analysis of HtrA1 reveal an N-terminal IGFBP/Kazal tandem domain, a protease active site in a competent conformation in the absence of substrate, and a trimeric arrangement; neither IGFBP- nor Kazal-like modules retain prototype protein function, and the active site data support a conformational selection model for substrate binding. X-ray crystallography, SAXS, enzymatic activity assays, binding studies with domain deletion constructs Structure High 22578544
2015 HTRA1 degrades amyloid fibrils in an ATP-independent manner by solubilizing fibrils, disintegrating the fibrillar core, and allowing productive interaction of aggregated polypeptides with its active site; this activity reduces aggregate burden in a cellular model of cytoplasmic tau aggregation. In vitro fibril disaggregation assays, structural analysis, cellular tau aggregation model Nature Chemical Biology High 26436840
2016 HTRA1 missense mutations found in manifesting heterozygotes with CARASIL-like disease show markedly decreased protease activity and inhibit wild-type HTRA1 activity (dominant-negative effect); these mutants either fail to form trimers or carry mutations in domains critical for trimer-associated activation, whereas CARASIL-associated mutants do form trimers but have mutations outside activation domains. Casein protease activity assays, gel filtration chromatography for oligomeric state analysis, HTRA1 co-incubation experiments Neurology High 27164673
2018 HTRA1 cleaves the Notch ligand JAG1 within its intracellular domain, leading to JAG1 protein degradation; HTRA1 physically interacts with JAG1, thereby enhancing Delta/Notch signaling. Loss of HTRA1 in endothelial cells increases JAG1 and promotes hypersprouting angiogenesis, and HtrA1-deficient mice have diminished endothelial Notch signaling and denser, immature tumor vasculature. Co-immunoprecipitation, in vitro cleavage assay, siRNA knockdown and overexpression in endothelial cells, HtrA1-/- mouse tumor model, rescue with constitutively active Notch1 Oncogene High 29713059
2018 HTRA1 cleaves extracellular matrix proteins EFEMP1 and TSP1 (novel substrates), in addition to previously known substrates LTBP-1 and clusterin, in RPE cells with the AMD high-risk genotype. Proteomic comparison of RPE cells with/without AMD high-risk mutation, identification of HTRA1 cleavage targets by proteomics Aging Cell Medium 29730901
2018 HTRA1 is sequestered by Notch3 extracellular domain (Notch3ECD) deposits in CADASIL brain vessels, and the CADASIL brain vessel proteome shows enrichment of known HTRA1 substrates consistent with reduced HTRA1 activity; multiple HTRA1 substrates were validated in an in vitro proteolysis assay, linking CADASIL pathology to functional HTRA1 loss. Quantitative brain vessel proteomics from CADASIL patients vs. controls, comparison with HtrA1 knockout mouse proteome, in vitro proteolysis assay Acta Neuropathologica High 29725820
2019 HTRA1 is essential for vascular smooth muscle cell (VSMC) differentiation into the contractile phenotype; loss of HTRA1 increases JAG1 protein and NOTCH3 signaling and enhances TGF-β-SMAD2/3 signaling, leading to additive accumulation of HES/HEY repressors that suppress contractile VSMC marker genes and impair arterial vasoconstriction in Htra1-/- mice. Htra1-/- mouse model, VSMC differentiation assays, Western blot for JAG1/Notch3/TGFβ pathway, gene expression analysis, vasoconstriction functional assay Scientific Reports High 31796853
2019 Osteoclasts secrete HTRA1, which degrades osteoprotegerin (OPG); HTRA1 recognizes the three-dimensional structure of OPG and initially cleaves the amide bond between Leu90 and Gln91, then degrades OPG into small fragments, thereby suppressing OPG inhibition of RANKL-induced osteoclastogenesis. Mass spectrometry identification of OPG-degrading enzyme, in vitro cleavage assay with recombinant HTRA1 and OPG, mapping of cleavage site, DTT-reduction experiment, RAW 264.7 osteoclastogenesis assay Communications Biology High 30854478
2015 An anti-HtrA1 antibody forms a cage-like macromolecular complex with the HtrA1 catalytic domain trimer; three IgG molecules coordinate two HtrA1 trimers in a 636-kDa cage with six active sites pointing inward, achieving complete inhibition of enzyme activity through an allosteric mechanism involving surface-exposed loops B and C of the catalytic domain. Negative-stain EM, biochemical complex characterization, epitope mapping, enzymatic activity assays Biochemical Journal High 26385991
2011 Transgenic expression of human HTRA1 in mouse retinal pigment epithelium is sufficient to cause polypoidal choroidal vasculopathy (PCV), including branching choroidal vessel networks, polypoidal lesions, elastic laminae degeneration, tunica media degeneration, RPE atrophy, and photoreceptor degeneration; senescent HTRA1 transgenic mice develop occult CNV with upregulated VEGF. Transgenic mouse model with human HTRA1 expressed in RPE, fundus imaging, histology, immunohistochemistry, VEGF measurement Proceedings of the National Academy of Sciences High 21844367
2006 HtrA1 expression is upregulated by cisplatin and paclitaxel treatment, resulting in limited autoproteolysis and activation of HtrA1; active HtrA1 induces cell death in a serine protease-dependent manner, and downregulation of HtrA1 attenuates chemotherapy-induced cytotoxicity while forced expression enhances it. Forced expression and knockdown of HtrA1 in ovarian cancer cell lines, cell viability assays with cisplatin/paclitaxel, autoproteolysis analysis, protease-dead mutant (SA) controls Journal of Clinical Investigation High 16767218
2012 MiR-30e and miR-181d are posttranscriptional negative regulators of HTRA1 by binding to the 3' UTR of HTRA1 mRNA; in vivo overexpression of these miRNAs in Dicer-/- forebrain rescued radial glia proliferation defects caused by HTRA1 overexpression. Dicer conditional KO mouse, in vivo miRNA overexpression, luciferase reporter assay with HTRA1 3'UTR, rescue experiments Cell Death & Disease Medium 22854828
2017 HTRA1 inhibits canonical Wnt/β-catenin signaling in both paracrine and autocrine manners; HTRA1 forms a complex with β-catenin and reduces cell proliferation rates, and affects expression of several Wnt target genes. Wnt reporter assays, co-immunoprecipitation of HTRA1 with β-catenin, HTRA1 overexpression in colorectal cancer cells, cell proliferation assays Scientific Reports Medium 29269789
2013 TLR-4 activation by LPS induces HTRA1 expression through the NF-κB pathway; the NF-κB subunit p65 directly binds to the HTRA1 promoter at position -347, as demonstrated by dual-luciferase reporter and ChIP assays. Real-time PCR, ELISA, NF-κB inhibitors, siRNA, dual-luciferase reporter, chromatin immunoprecipitation (ChIP) Arthritis and Rheumatism Medium 23982886
2014 IFN-γ inhibits HTRA1 expression through activation of p38 MAPK/STAT1 pathway; STAT1 directly binds to the HTRA1 promoter after IFN-γ stimulation, as shown by dual-luciferase reporter and ChIP assays. Real-time PCR, Western blot, CIA mouse model with IFN-γ KO, dual-luciferase reporter, ChIP Journal of Immunology Medium 24907345
2014 HtrA1 is required for normal placentation in mice; HtrA1-/- mice show intrauterine growth retardation with small placentas due to reduced junctional zone and aberrant labyrinth vascularization, caused by decreased differentiation of Tpbpa-positive trophoblast precursors, fewer spiral artery-associated trophoblast giant cells, and impaired maternal artery remodeling. HtrA1-/- mouse model, histology, immunostaining for trophoblast markers, morphometric analysis of maternal arteries Developmental Biology High 25446274
2021 Rare loss-of-function variants in the HTRA1 protease domain (amino acids 204-364) associate with increased white matter hyperintensity volume; most identified protease domain variants result in markedly reduced protease activity in biochemical assays; EGFL8 was identified as a direct substrate of HTRA1. Whole-exome sequencing gene burden tests, domain-specific burden analysis, in vitro protease activity assays of individual variants, substrate identification Brain High 34626176
2024 HTRA1 inhibits aggregation of α-synuclein, FUS, and TDP-43; the protease domain of HTRA1 is necessary and sufficient for this activity but the activity is proteolysis-independent. HTRA1 disaggregates preformed α-syn fibrils, rendering them seeding-incompetent, by targeting the NAC domain of α-syn. Reducing HTRA1 expression promotes α-syn seeding, and HTRA1 detoxifies α-syn fibrils and prevents hyperphosphorylated α-syn accumulation in primary neurons. In vitro aggregation inhibition and fibril disaggregation assays, protease-dead mutant and domain deletion constructs, α-syn seeding assays, primary neuron toxicity assays, HTRA1 knockdown Nature Communications High 38499535
2016 HTRA1 is epigenetically silenced in HCT116 colon carcinoma cells via the epigenetic adaptor protein MBD2; depletion of HTRA1 causes centrosome amplification and polyploidy in colon cancer cells and primary mouse embryonic fibroblasts. Epigenetic analysis in cancer cell lines, MBD2 involvement demonstrated, HTRA1 siRNA knockdown with centrosome and ploidy analysis BMC Cancer Medium 27388476
2020 RUNX2 co-operates with EGR1 to transcriptionally repress HTRA1 through Htra1 enhancers; RUNX2 and EGR1 physically co-occupy seven verified HTRA1 enhancers as shown by Re-ChIP assay, and their combined action represses HTRA1 expression while promoting osteoblast differentiation markers. ChIP-seq, RNA-seq, dual-luciferase enhancer assays, Re-ChIP, siRNA knockdown, alizarin red and ALP staining Journal of Cellular Physiology Medium 32324256

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science (New York, N.Y.) 643 17053109
2011 HTRA proteases: regulated proteolysis in protein quality control. Nature reviews. Molecular cell biology 394 21326199
2009 Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease. The New England journal of medicine 368 19387015
2005 The role of human HtrA1 in arthritic disease. The Journal of biological chemistry 234 16377621
2005 Implications of the serine protease HtrA1 in amyloid precursor protein processing. Proceedings of the National Academy of Sciences of the United States of America 177 15855271
2004 The S. cerevisiae HtrA-like protein Nma111p is a nuclear serine protease that mediates yeast apoptosis. Journal of cell science 173 14657274
2002 The HtrA1 serine protease is down-regulated during human melanoma progression and represses growth of metastatic melanoma cells. Oncogene 167 12242667
2004 A candidate tumor suppressor HtrA1 is downregulated in ovarian cancer. Oncogene 145 14716297
2005 Structure and function of HtrA family proteins, the key players in protein quality control. Journal of biochemistry and molecular biology 142 15943900
2011 Increased expression of multifunctional serine protease, HTRA1, in retinal pigment epithelium induces polypoidal choroidal vasculopathy in mice. Proceedings of the National Academy of Sciences of the United States of America 137 21844367
2006 Serine protease HtrA1 modulates chemotherapy-induced cytotoxicity. The Journal of clinical investigation 122 16767218
2003 Distribution of the serine protease HtrA1 in normal human tissues. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 106 14500695
2004 Role of HtrA in the virulence and competence of Streptococcus pneumoniae. Infection and immunity 101 15155668
2016 Distinct molecular mechanisms of HTRA1 mutants in manifesting heterozygotes with CARASIL. Neurology 97 27164673
2010 Genetic and functional dissection of HTRA1 and LOC387715 in age-related macular degeneration. PLoS genetics 96 20140183
2005 Role of HtrA in growth and competence of Streptococcus mutans UA159. Journal of bacteriology 93 15838029
2010 Role of HTRA1, a serine protease, in the progression of articular cartilage degeneration. Histology and histopathology 91 20238298
2021 Serine Protease HTRA1 as a Novel Target Antigen in Primary Membranous Nephropathy. Journal of the American Society of Nephrology : JASN 90 33952630
2010 HtrA proteins as targets in therapy of cancer and other diseases. Expert opinion on therapeutic targets 90 20469960
2015 Determinants of amyloid fibril degradation by the PDZ protease HTRA1. Nature chemical biology 88 26436840
2012 Structural and functional analysis of HtrA1 and its subdomains. Structure (London, England : 1993) 86 22578544
2018 HTRA1, an age-related macular degeneration protease, processes extracellular matrix proteins EFEMP1 and TSP1. Aging cell 82 29730901
2012 Human high temperature requirement serine protease A1 (HTRA1) degrades tau protein aggregates. The Journal of biological chemistry 80 22535953
2007 Structural and functional analysis of the PDZ domains of human HtrA1 and HtrA3. Protein science : a publication of the Protein Society 79 17962403
2006 Serine proteases HTRA1 and HTRA3 are down-regulated with increasing grades of human endometrial cancer. Gynecologic oncology 79 16650464
2005 Role for HtrA in stress induction and virulence potential in Listeria monocytogenes. Applied and environmental microbiology 77 16085809
1997 Salmonella typhimurium aroA, htrA, and aroD htrA mutants cause progressive infections in athymic (nu/nu) BALB/c mice. Infection and immunity 76 9119506
2012 The HtrA protease from Streptococcus pneumoniae digests both denatured proteins and the competence-stimulating peptide. The Journal of biological chemistry 73 23012372
2002 Role of the htrA gene in Klebsiella pneumoniae virulence. Infection and immunity 71 12183518
2015 Characterisation of worldwide Helicobacter pylori strains reveals genetic conservation and essentiality of serine protease HtrA. Molecular microbiology 68 26568477
2018 CADASIL brain vessels show a HTRA1 loss-of-function profile. Acta neuropathologica 67 29725820
2016 Recombinant Haplotypes Narrow the ARMS2/HTRA1 Association Signal for Age-Related Macular Degeneration. Genetics 63 27879347
2007 HtrA1 inhibits mineral deposition by osteoblasts: requirement for the protease and PDZ domains. The Journal of biological chemistry 60 18156628
1997 HtrA heat shock protease interacts with phospholipid membranes and undergoes conformational changes. The Journal of biological chemistry 60 9083020
2017 Structural insights into the activation mechanisms of human HtrA serine proteases. Archives of biochemistry and biophysics 59 28396256
2014 Overexpression of HtrA1 and exposure to mainstream cigarette smoke leads to choroidal neovascularization and subretinal deposits in aged mice. Investigative ophthalmology & visual science 57 25205867
2009 Expression of human HtrA1, HtrA2, HtrA3 and TGF-beta1 genes in primary endometrial cancer. Oncology reports 50 19424634
2004 The serine protease HtrA1 is upregulated in the human placenta during pregnancy. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 49 15208355
2006 Analysis of HtrA1 serine protease expression in human lung cancer. Anticancer research 46 17094466
2007 HtrA1: a novel regulator of physiological and pathological matrix mineralization? Biochemical Society transactions 42 17635117
2018 Elevated HTRA1 and HTRA4 in severe preeclampsia and their roles in trophoblast functions. Molecular medicine reports 41 30015931
2010 Expression and functional significance of HtrA1 loss in endometrial cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 41 21098697
2009 Deg/HtrA proteases as components of a network for photosystem II quality control in chloroplasts and cyanobacteria. Research in microbiology 41 19732828
2020 Campylobacter jejuni Serine Protease HtrA Cleaves the Tight Junction Component Claudin-8. Frontiers in cellular and infection microbiology 39 33364202
2017 Bacterial serine protease HtrA as a promising new target for antimicrobial therapy? Cell communication and signaling : CCS 39 28069057
1998 The Haemophilus influenzae HtrA protein is a protective antigen. Infection and immunity 39 9488373
2022 The Phenotypic Course of Age-Related Macular Degeneration for ARMS2/HTRA1: The EYE-RISK Consortium. Ophthalmology 37 35240203
2016 HtrA Is Important for Stress Resistance and Virulence in Haemophilus parasuis. Infection and immunity 36 27217419
2012 MiR-30e and miR-181d control radial glia cell proliferation via HtrA1 modulation. Cell death & disease 36 22854828
2013 HtrA1 in human urothelial bladder cancer: a secreted protein and a potential novel biomarker. International journal of cancer 35 23712470
2013 Lipopolysaccharide increases the incidence of collagen-induced arthritis in mice through induction of protease HTRA-1 expression. Arthritis and rheumatism 35 23982886
2004 Three SNPs in the GSTO1, GSTO2 and PRSS11 genes on chromosome 10 are not associated with age-at-onset of Alzheimer's disease. Neurobiology of aging 35 15917099
2022 Exploring the contribution of ARMS2 and HTRA1 genetic risk factors in age-related macular degeneration. Progress in retinal and eye research 34 36581531
2021 HTRA family proteins in pregnancy outcome. Tissue & cell 34 33915357
2018 Function of Serine Protease HtrA in the Lifecycle of the Foodborne Pathogen Campylobacter jejuni. European journal of microbiology & immunology 34 30345086
2017 Low HtrA1 expression in patients with long‑standing ulcerative colitis and colorectal cancer. Oncology reports 34 28586045
2014 BMP-2, hypoxia, and COL1A1/HtrA1 siRNAs favor neo-cartilage hyaline matrix formation in chondrocytes. Tissue engineering. Part C, Methods 34 24957638
2021 Whole-exome sequencing reveals a role of HTRA1 and EGFL8 in brain white matter hyperintensities. Brain : a journal of neurology 33 34626176
2019 Establishment of serine protease htrA mutants in Helicobacter pylori is associated with secA mutations. Scientific reports 33 31409845
2014 Abnormal development of placenta in HtrA1-deficient mice. Developmental biology 33 25446274
2004 Pattern of expression of HtrA1 during mouse development. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 33 15557215
2018 Inactivation of the serine protease HTRA1 inhibits tumor growth by deregulating angiogenesis. Oncogene 30 29713059
2014 The inhibitory effect of IFN-γ on protease HTRA1 expression in rheumatoid arthritis. Journal of immunology (Baltimore, Md. : 1950) 30 24907345
2019 HTRA1 synergizes with oxidized phospholipids in promoting inflammation and macrophage infiltration essential for ocular VEGF expression. PloS one 29 31100080
2016 The function of the DegP (HtrA) protein: Protease versus chaperone. IUBMB life 29 27670951
2005 Serine protease HtrA1 is developmentally regulated in trophoblast and uterine decidual cells during placental formation in the mouse. Developmental dynamics : an official publication of the American Association of Anatomists 29 15861393
2014 Inhibiting Helicobacter pylori HtrA protease by addressing a computationally predicted allosteric ligand binding site. Chemical science 28 26819700
2019 HtrA-mediated selective degradation of DNA uptake apparatus accelerates termination of pneumococcal transformation. Molecular microbiology 27 31396996
2010 Serine protease HtrA1 expression in human hepatocellular carcinoma. Hepatobiliary & pancreatic diseases international : HBPD INT 26 20943460
2023 Inhibiting HIF-1 signaling alleviates HTRA1-induced RPE senescence in retinal degeneration. Cell communication and signaling : CCS 25 37316948
2021 HtrA family proteases of bacterial pathogens: pros and cons for their therapeutic use. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases 23 33359376
2021 Cross-sectional associations among P3NP, HtrA, Hsp70, Apelin and sarcopenia in Taiwanese population. BMC geriatrics 23 33743591
2019 Mycobacterium smegmatis HtrA Blocks the Toxic Activity of a Putative Cell Wall Amidase. Cell reports 23 31116989
2004 Regulation of htrA expression in Yersinia enterocolitica. FEMS microbiology letters 23 14987769
2021 Ongoing controversies and recent insights of the ARMS2-HTRA1 locus in age-related macular degeneration. Experimental eye research 22 33930395
2009 HTRA1 promoter polymorphism and risk of age-related macular degeneration: a meta-analysis. Annals of epidemiology 22 19375943
2004 Expression of the Staphylococcus aureus surface proteins HtrA1 and HtrA2 in Lactococcus lactis. FEMS microbiology letters 22 15321674
2017 High-Temperature Requirement A1 (Htra1) - A Novel Regulator of Canonical Wnt Signaling. Scientific reports 21 29269789
2016 Epigenetic silencing of serine protease HTRA1 drives polyploidy. BMC cancer 21 27388476
2015 Borrelia burgdorferi HtrA: evidence for twofold proteolysis of outer membrane protein p66. Molecular microbiology 21 26370492
2014 The HtrA-like protease CD3284 modulates virulence of Clostridium difficile. Infection and immunity 21 25047848
2024 HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species. Nature communications 20 38499535
2022 Melatonin regulates trophoblast pyroptosis, invasion and migration in preeclampsia by inhibiting HtrA1 transcription through the microRNA-520c-3p/SETD7 axis. American journal of reproductive immunology (New York, N.Y. : 1989) 20 35137483
2021 Identification of Desmoglein-2 as a novel target of Helicobacter pylori HtrA in epithelial cells. Cell communication and signaling : CCS 20 34742300
2021 Interplay between HTRA1 and classical signalling pathways in organogenesis and diseases. Saudi journal of biological sciences 20 35531175
2019 Murine osteoclasts secrete serine protease HtrA1 capable of degrading osteoprotegerin in the bone microenvironment. Communications biology 20 30854478
2019 Loss of the serine protease HTRA1 impairs smooth muscle cells maturation. Scientific reports 20 31796853
2018 HtrA of Borrelia burgdorferi Leads to Decreased Swarm Motility and Decreased Production of Pyruvate. mBio 19 29991588
2021 Heterozygous HTRA1 nonsense or frameshift mutations are pathogenic. Brain : a journal of neurology 18 34270682
2020 Importance of two PDZ domains for the proteolytic and chaperone activities of Helicobacter pylori serine protease HtrA. Cellular microbiology 18 33277762
2023 Trimer stability of Helicobacter pylori HtrA is regulated by a natural mutation in the protease domain. Medical microbiology and immunology 17 37183214
2020 RUNX2 co-operates with EGR1 to regulate osteogenic differentiation through Htra1 enhancers. Journal of cellular physiology 17 32324256
2014 Mutation in the HTRA1 gene in a patient with degenerated spine as a component of CARASIL syndrome. Turkish neurosurgery 17 24535794
2021 The interplay of oxidative stress and ARMS2-HTRA1 genetic risk in neovascular AMD. Vessel plus 16 34017939
2021 Function, molecular mechanisms, and therapeutic potential of bacterial HtrA proteins: An evolving view. Computational and structural biotechnology journal 16 34976310
2019 Association of HTRA1 and ARMS2 gene polymorphisms with response to intravitreal ranibizumab among neovascular age-related macular degenerative subjects. Human genomics 16 30795802
2015 The trimeric serine protease HtrA1 forms a cage-like inhibition complex with an anti-HtrA1 antibody. The Biochemical journal 16 26385991
2017 Uptake of the proteins HTRA1 and HTRA2 by cells mediated by calcium phosphate nanoparticles. Beilstein journal of nanotechnology 15 28326227
2023 HTRA1 in Placental Cell Models: A Possible Role in Preeclampsia. Current issues in molecular biology 14 37232715
2018 Heterozygous HTRA1 missense mutation in CADASIL-like family disease. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 14 29561953