Affinage

HTRA1

Serine protease HTRA1 · UniProt Q92743

Length
480 aa
Mass
51.3 kDa
Annotated
2026-06-10
100 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HTRA1 is a homotrimeric, secreted serine protease that regulates extracellular signaling and matrix homeostasis by proteolytically processing a broad set of substrates, and that secondarily moonlights as a chaperone-like disaggregase and microtubule-associated protein (PMID:14973287, PMID:18156628, PMID:38499535, PMID:19470753). Its protease domain binds and antagonizes TGF-β family ligands (BMP4, GDF5, TGFβs, activin) in a proteolysis-dependent manner to block receptor activation (PMID:14973287), and it cleaves extracellular matrix and matricellular substrates including decorin, fibronectin, matrix Gla protein, EFEMP1, TSP1, and LTBP-1, with substrate-specific dependence on its regulatory PDZ domain (PMID:18156628, PMID:29730901). Through cleavage of the Notch ligand JAG1 within its intracellular domain, HTRA1 promotes JAG1 degradation and tunes Notch3 signaling, and loss of HTRA1 in vascular smooth muscle cells de-represses both JAG1/NOTCH3 and TGFβ-SMAD2/3 signaling, driving HES/HEY-mediated repression of contractile genes and impaired vasoconstriction (PMID:29713059, PMID:31796853); HTRA1 also restrains canonical Wnt/β-catenin signaling and forms a complex with β-catenin (PMID:29269789). Catalytically, HTRA1 adopts an active-competent conformation even without substrate, and trimer activation proceeds through allosteric inter-monomer communication independent of the PDZ domain (PMID:22578544, PMID:29093542). Beyond proteolysis, HTRA1 disaggregates amyloidogenic protein fibrils—degrading aggregated tau and, via its protease domain in a proteolysis-independent mode, disaggregating α-synuclein, FUS, and TDP-43 into non-seeding, non-toxic species (PMID:22535953, PMID:38499535)—and associates with microtubules and tubulin via its PDZ domain to limit cell motility (PMID:19470753). HTRA1 is induced by cellular stress and chemotherapeutics to drive protease-dependent cell death and p38 MAPK-dependent senescence (PMID:16767218, PMID:23623979), and is essential in vivo for trophoblast differentiation and placental vascular remodeling (PMID:25446274).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2004 High

    Established HTRA1 as a negative regulator of TGF-β family signaling, defining its first signaling role and showing this depends on its protease activity.

    Evidence GST-pulldown, domain deletion mutants, and C2C12 signaling assays with chick embryo misexpression

    PMID:14973287

    Open questions at the time
    • Whether inhibition reflects ligand cleavage versus stoichiometric sequestration not fully resolved
    • Physiological substrates among the tested ligands not pinpointed
  2. 2005 Medium

    Linked HTRA1 proteolysis to amyloid biology by showing it degrades APP fragments and colocalizes with β-amyloid deposits.

    Evidence In vitro protease assay, astrocyte supernatant analysis with HtrA1 inhibitor, human brain immunofluorescence

    PMID:15855271

    Open questions at the time
    • Cleavage sites and physiological relevance to Aβ clearance not defined
    • Single lab
  3. 2007 High

    Defined HTRA1 as an ECM-processing protease and dissected differential PDZ-domain requirements across substrates, linking it to mineralization control.

    Evidence Osteoblast overexpression/knockdown plus recombinant domain-mutant in vitro cleavage of decorin, fibronectin, and MGP

    PMID:18156628

    Open questions at the time
    • Mechanistic basis for PDZ-dependence of MGP versus PDZ-independence of decorin/fibronectin unclear
    • Cleavage product fate in vivo not tracked
  4. 2009 High

    Revealed a non-proteolytic cytoskeletal role: HTRA1 binds tubulin via its PDZ domain, promotes microtubule assembly, and suppresses cell motility.

    Evidence Co-sedimentation, co-purification, direct tubulin binding, IP, in vitro assembly, and KD/OE motility assays

    PMID:19470753

    Open questions at the time
    • Relationship between cytoplasmic microtubule role and secreted protease function unresolved
    • Whether protease activity acts on microtubule-associated substrates unknown
  5. 2006 Medium

    Connected HTRA1 to stress-induced cell fate, showing chemotherapeutics trigger its autoproteolytic activation and protease-dependent cell death.

    Evidence Gain/loss-of-function in cancer cells with protease-inactive mutant control and autoproteolysis Western blots

    PMID:16767218

    Open questions at the time
    • Intracellular substrates mediating death not identified
    • Single lab
  6. 2010 Medium

    Implicated HTRA1 in mTOR pathway control via direct binding and cleavage of TSC2.

    Evidence Co-IP, in vitro/in vivo cleavage, and downstream 4E-BP1/S6K phosphorylation readouts

    PMID:20671064

    Open questions at the time
    • How a secreted protease accesses cytoplasmic TSC2 not reconciled
    • Single lab
  7. 2012 High

    Defined the structural basis of HTRA1 catalysis, showing the active site is competent without substrate, supporting a conformational-selection model.

    Evidence X-ray crystallography, SAXS, and enzymatic assays with domain variants

    PMID:22578544

    Open questions at the time
    • Functional role of the IGFBP-/Kazal tandem module not established
    • Full-length trimer architecture not solved
  8. 2012 Medium

    Extended HTRA1 into tauopathy by showing it degrades aggregated/fibrillar tau and is upregulated by elevated tau.

    Evidence In vitro fibrillar-tau degradation, HTRA1-overexpressing neuronal cells, patient brain analysis

    PMID:22535953

    Open questions at the time
    • Mechanism of accessing intracellular tau unclear
    • Single lab
  9. 2013 Medium

    Linked HTRA1 to oxidative-stress-induced senescence through protease-dependent p38 MAPK activation.

    Evidence WT vs S328A protease-inactive HtrA1 in H2O2-treated MEFs/ARPE-19 with p38 inhibitor and HtrA1-/- comparison

    PMID:23623979

    Open questions at the time
    • Substrate upstream of p38 not identified
    • Single lab
  10. 2017 Medium

    Established the trimer activation mechanism: allosteric inter-monomer communication, PDZ-independent, gates catalysis and fibril degradation.

    Evidence Allosteric assays, inhibitor binding with communication-defective mutants, fibril degradation assays

    PMID:29093542

    Open questions at the time
    • Structural residues mediating communication not fully mapped
    • Single lab
  11. 2017 Medium

    Identified HTRA1 as an inhibitor of canonical Wnt/β-catenin signaling acting both autocrine and paracrine.

    Evidence Wnt luciferase reporter, HTRA1–β-catenin co-IP, proliferation assays with OE/KD

    PMID:29269789

    Open questions at the time
    • Whether β-catenin is a cleavage substrate or binding partner only is unclear
    • Single co-IP without reciprocal validation
  12. 2018 High

    Defined the JAG1/Notch axis: HTRA1 cleaves JAG1 to enhance Delta/Notch signaling and regulate endothelial VEGFR2, establishing a vascular signaling function.

    Evidence Physical interaction, in vitro/in vivo JAG1 cleavage, endothelial KD/OE, constitutively active Notch1 rescue, HtrA1-/- mice

    PMID:29713059

    Open questions at the time
    • JAG1 cleavage site within intracellular domain not mapped
    • Topological basis for intracellular cleavage by a secreted protease unresolved
  13. 2018 Medium

    Expanded the secreted-substrate repertoire to EFEMP1 and TSP1 in retinal pigment epithelium, linking genotype to altered ECM processing.

    Evidence RPE proteomics by HTRA1 genotype plus in vitro cleavage of novel substrates

    PMID:29730901

    Open questions at the time
    • Functional consequences of EFEMP1/TSP1 cleavage in vivo not established
    • Single lab
  14. 2018 Medium

    Connected HTRA1 to cerebral small-vessel disease, showing HTRA1 sequestration on Notch3ECD deposits in CADASIL and loss-of-function substrate accumulation.

    Evidence Quantitative brain vessel proteomics, colocalization, HTRA1-/- proteome comparison, in vitro proteolysis

    PMID:29725820

    Open questions at the time
    • Causal contribution of sequestration to disease progression not proven
    • Single lab
  15. 2019 Medium

    Integrated HTRA1's JAG1/NOTCH3 and TGFβ functions into a vascular phenotype, explaining how its loss drives immature VSMCs and impaired vasoconstriction.

    Evidence HtrA1-/- mice, VSMC differentiation, Notch3/TGFβ pathway manipulation, ex vivo vasoconstriction

    PMID:31796853

    Open questions at the time
    • Relative contribution of the two pathways not quantified
    • Single lab
  16. 2024 High

    Defined a proteolysis-independent disaggregase activity: the HTRA1 protease domain alone inhibits and reverses α-synuclein, FUS, and TDP-43 aggregation into non-toxic species.

    Evidence In vitro aggregation/disaggregation/seeding assays, domain deletions, HTRA1 KD, primary neuron toxicity

    PMID:38499535

    Open questions at the time
    • Structural basis for proteolysis-independent NAC-domain targeting unresolved
    • In vivo neuroprotective relevance not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How HTRA1's multiple compartmental activities—secreted ECM/ligand proteolysis, cytoplasmic/intracellular substrate cleavage, microtubule binding, and proteolysis-independent disaggregation—are coordinated within a single protein remains unresolved.
  • No unified model reconciling extracellular and intracellular pools
  • Mechanism switching between proteolytic and disaggregase modes unknown
  • Spatial regulation of substrate selection undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016787 hydrolase activity 4 GO:0098772 molecular function regulator activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005576 extracellular region 3 GO:0005634 nucleus 1 GO:0005815 microtubule organizing center 1 GO:0005856 cytoskeleton 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1474244 Extracellular matrix organization 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
CTNNB1JAG1SLC7A11TSC2TUBATUBB

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 HtrA1 inhibits TGF-β family signaling by binding to a broad range of TGF-β family proteins (including BMP4, GDF5, TGFβs, and activin) via its protease domain and a linker region, preventing receptor activation; inhibition of TGFβ signaling is dependent on the proteolytic activity of HtrA1. GST-pulldown assay, deletion mutant analysis, cell-based signaling assay (C2C12 cells), chick embryo misexpression Development High 14973287
2005 HtrA1 directly degrades fragments of amyloid precursor protein (APP); an HtrA1 inhibitor causes accumulation of Aβ in astrocyte cell culture supernatants, and HtrA1 colocalizes with β-amyloid deposits in human brain samples. In vitro protease assay, cell culture supernatant analysis with HtrA1 inhibitor, immunofluorescence colocalization in human brain tissue Proceedings of the National Academy of Sciences of the United States of America Medium 15855271
2007 HtrA1 inhibits mineral deposition by osteoblasts; both the protease domain and the PDZ domain are required for this inhibitory effect. HtrA1 cleaves extracellular matrix proteins decorin, fibronectin, and matrix Gla protein (MGP); cleavage of MGP requires both the protease and PDZ domains, whereas cleavage of decorin and fibronectin does not require the PDZ domain. Type I collagen is not cleaved. Overexpression and siRNA knockdown in 2T3 osteoblasts, recombinant HtrA1 domain mutant in vitro cleavage assays, mineralization assays The Journal of biological chemistry High 18156628
2009 Human HtrA1 associates with microtubules in a PDZ domain-dependent and nocodazole-sensitive manner; it localizes to centrosomes and newly polymerized microtubules during assembly, promotes microtubule assembly in vitro, cosediments and copurifies with microtubules, and directly binds purified α- and β-tubulins. Downregulation of HtrA1 promotes cell motility while overexpression attenuates it. Immunofluorescence, microtubule co-sedimentation assay, co-purification, immunoprecipitation (endogenous HtrA1 pulling down α-, β-, γ-tubulin), in vitro microtubule assembly assay, cell motility assay with KD/OE Molecular and cellular biology High 19470753
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 modulates chemotherapy-induced cytotoxicity. Forced expression and downregulation of HtrA1 in cancer cell lines, cytotoxicity assays, protease-inactive mutant comparison, Western blot for autoproteolysis The Journal of clinical investigation Medium 16767218
2012 Human HTRA1 degrades aggregated and fibrillar tau protein; neuronal cells with elevated HTRA1 accumulate less tau and neurofibrillary tangles; HTRA1 mRNA and activity are upregulated in response to elevated tau concentrations. In vitro degradation assay with aggregated/fibrillar tau, cell-based assay with HTRA1 overexpression, patient brain analysis, activity measurement The Journal of biological chemistry Medium 22535953
2012 Crystal structures and SAXS analysis of HtrA1 reveal a rare tandem of IGFBP- and Kazal-like modules in the N-terminal domain; the protease active site adopts a competent conformation in the absence of substrate or inhibitor, suggesting a two-state equilibrium/conformational selection model for substrate binding. The N-terminal IGFBP- and Kazal-like modules have no detectable effect on protease activity. X-ray crystallography, SAXS, enzymatic activity assays, binding studies with domain variants Structure High 22578544
2010 HtrA1 directly interacts with TSC2 (tuberin) but not TSC1 (hamartin); HtrA1 cleaves TSC2 both in vitro and in vivo, and alterations in HtrA1 expression cause changes in phosphorylation status of TSC2 downstream targets 4E-BP1 and S6K. Co-immunoprecipitation, colocalization, in vitro cleavage assay, in vivo cleavage assay, Western blot for downstream phosphorylation Molecular cancer research Medium 20671064
2013 HtrA1 is induced by oxidative stress and promotes premature cell senescence through the p38 MAPK pathway in a protease activity-dependent manner; protease-inactive HtrA1 (S328A mutant) does not accelerate senescence, and HtrA1-induced senescence is abrogated by p38 MAPK inhibition. Transient transfection of wild-type vs. protease-inactive HtrA1, H2O2-induced senescence in MEFs and ARPE-19 cells, SA-β-galactosidase assay, p38 MAPK inhibitor, HtrA1-/- MEFs comparison Experimental eye research Medium 23623979
2017 HtrA1 activation is regulated by an allosteric inter-monomer communication mechanism within its trimer, independent of the PDZ domain. Inhibitor binding is precluded if HtrA1 monomers cannot communicate with each other. The HtrA1 trimer degrades complex extracellular fibrils including tubulin, amyloid beta, and tau. Biochemical allosteric assays, inhibitor binding studies with communication-defective mutants, in vitro fibril degradation assays Scientific reports Medium 29093542
2018 HTRA1 cleaves the Notch ligand JAG1 within its intracellular domain, leading to JAG1 protein degradation and enhancement of Delta/Notch signaling; HTRA1 physically interacts with JAG1. In HtrA1-deficient mice, endothelial Notch signaling is diminished and VEGF receptor-2 expression is increased in endothelial cells. Physical interaction assay, in vitro/in vivo cleavage of JAG1, siRNA knockdown and forced expression of HTRA1 in endothelial cells, constitutively active Notch1 rescue experiment, HtrA1-/- mouse analysis Oncogene High 29713059
2018 HTRA1 processes extracellular matrix proteins EFEMP1 and TSP1 (novel substrates), in addition to previously known substrates LTBP-1 and clusterin, in retinal pigment epithelium cells. Proteomic comparison of RPE cells with/without high-risk HTRA1 genotype, in vitro HTRA1 cleavage assays for novel substrates Aging cell Medium 29730901
2018 CADASIL brain vessels accumulate HTRA1 protein (4.9-fold enriched) co-localizing with Notch3ECD deposits, consistent with HTRA1 sequestration. Comparison with HTRA1 knockout mouse brain vessel proteome reveals 18 overlapping enriched proteins, several of which are confirmed as novel HTRA1 substrates by in vitro proteolysis assay, consistent with loss of HTRA1 function in CADASIL. Quantitative brain vessel proteomics, colocalization, HTRA1-/- mouse proteome comparison, in vitro proteolysis assay Acta neuropathologica Medium 29725820
2019 Loss of HTRA1 in vascular smooth muscle cells (VSMCs) increases JAG1 protein levels and NOTCH3 signaling activity, and also enhances TGFβ-SMAD2/3 signaling. Combined over-activation of NOTCH3 and TGFβ pathways leads to additive accumulation of HES/HEY transcriptional repressors, repressing contractile VSMC marker genes and resulting in an immature VSMC phenotype with impaired arterial vasoconstriction in Htra1-deficient mice. HtrA1-/- mouse analysis, VSMC differentiation assays, Notch3 and TGFβ pathway activation/inhibition, ex vivo vasoconstriction assay Scientific reports Medium 31796853
2017 HTRA1 inhibits canonical Wnt/β-catenin signaling in both paracrine and autocrine manners; HTRA1 forms a complex with β-catenin and reduces the proliferation rates of cells, affecting expression of several Wnt target genes. Luciferase reporter assay for Wnt activity, co-immunoprecipitation of HTRA1 and β-catenin, cell proliferation assay, overexpression and knockdown Scientific reports Medium 29269789
2014 HtrA1 plays important roles in trophoblast differentiation from Tpbpa-positive precursors in the ectoplacental cone. HtrA1-/- mice show intrauterine growth retardation with reduced junctional zone size, aberrant labyrinth vascularization, decreased spongiotrophoblasts and glycogen trophoblasts, and impaired maternal artery remodeling. HtrA1-/- mouse knockout analysis, histology, immunostaining for trophoblast markers, vascular morphometry Developmental biology Medium 25446274
2012 MiR-30e and miR-181d are posttranscriptional negative regulators of HtrA1 by binding to its 3' UTR; overexpression of HtrA1 in the developing forebrain recapitulates aspects of the Dicer-/- phenotype affecting radial glia proliferation, and in vivo overexpression of miR-30e and miR-181d in Dicer-/- forebrain rescues RG proliferation defects. 3'UTR luciferase reporter assay, in vivo rescue experiment in Dicer-/- mice, forebrain overexpression of HtrA1 Cell death & disease Medium 22854828
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 SW480 cells and primary MEFs. MBD2 knockdown/chromatin analysis, HTRA1 depletion by siRNA, centrosome counting, ploidy analysis BMC cancer Medium 27388476
2014 IFN-γ negatively controls HTRA1 expression through activation of the p38 MAPK/STAT1 pathway; STAT1 directly binds the HTRA1 promoter after IFN-γ stimulation. Neutralization of HTRA1 reversed enhanced collagen-induced arthritis (CIA) frequency and severity in IFN-γ-deficient mice. Dual luciferase reporter assay, chromatin immunoprecipitation (ChIP), p38 MAPK pathway inhibition, IFN-γ-/- mouse model of CIA, anti-HTRA1 antibody neutralization Journal of immunology Medium 24907345
2015 The trimeric HtrA1 catalytic domain forms a cage-like inhibition complex with antibody 94 (IgG94): one Fab binds peripherally to each protomer via loops B and C of the catalytic domain, suggesting an allosteric inhibition mechanism. The IgG94 complex (636 kDa) consists of three centrally located IgG molecules coordinating two HtrA1_Cat trimers with all six active sites pointing inward. Negative-staining EM, biochemical complex characterization, epitope mapping, enzymatic activity assays The Biochemical journal Medium 26385991
2018 HTRA1 is identified as a novel podocyte antigen in a subset of patients with primary membranous nephropathy; anti-HTRA1 autoantibodies are predominantly IgG4, and HTRA1 is specifically detected within immune deposits in affected kidney tissue. Immunoblotting of glomerular proteins, differential immunoprecipitation, mass spectrometry, laser-capture microdissection, protein fragment microarray, biopsy immunostaining Journal of the American Society of Nephrology Medium 33952630
2024 HTRA1 inhibits aggregation of α-synuclein, FUS, and TDP-43; disaggregates preformed α-syn fibrils and converts them into non-seeding, non-toxic species; reduces endogenous α-syn seeding when HTRA1 is knocked down; targets the NAC domain of α-syn; and detoxifies α-syn fibrils in primary neurons. The protease domain is necessary and sufficient for inhibiting aggregation, but this activity is proteolytically independent. In vitro aggregation inhibition assay, fibril disaggregation assay, seeding assay, HTRA1 knockdown cell assay, domain deletion mutants, primary neuron toxicity assay Nature communications High 38499535
2008 Processed forms of HtrA1 are found intracellularly and intranuclearly; the active intranuclear form has an apparent molecular weight of ~29 kDa. HtrA1 is found associated with HPV E6 and E7 proteins, and HPV E6/E7 expression is associated with post-transcriptional upregulation of HtrA1 (notably the nuclear form). Cellular fractionation, immunoblotting for HtrA1 isoforms, co-immunoprecipitation with HPV E6/E7 Journal of cellular biochemistry Low 18452160
2020 RUNX2 co-operates with EGR1 to co-repress Htra1 expression; RUNX2 binds to Htra1 enhancers (seven validated by dual-luciferase assay), and Re-ChIP assays confirm co-occupancy of RUNX2 and EGR1 at these sites. Co-repression of Htra1 by RUNX2/EGR1 is associated with increased expression of osteoblast differentiation markers. ChIP-seq, dual-luciferase enhancer assays, Re-ChIP, RNA-seq, siRNA knockdown Journal of cellular physiology Medium 32324256
2024 HTRA1 interacts with SLC7A11 (xCT) through its Kazal structural domain and upregulates SLC7A11 expression, thereby inhibiting ferroptosis and contributing to chemoresistance to 5-FU/L-OHP in colorectal cancer cells. Co-immunoprecipitation, domain mapping (Kazal domain), gain/loss-of-function, ROS and MDA measurement, electron microscopy for mitochondria, cell viability assays Cell death discovery Low 38740771
2018 HtrA1 regulates astrocyte differentiation and injury response: genetic deletion of HtrA1 during gliogenesis accelerates astrocyte differentiation, and HtrA1-ablated astrocytes show altered chondroitin sulfate proteoglycan expression, inhibition of neurite extension, and elevated TGF-β family proteins. Brain injury induces HtrA1 in reactive astrocytes and loss of HtrA1 impairs wound closure. HtrA1 genetic deletion in mice, astrocyte culture with HtrA1 ablation, neurite extension assay, injury response assay, immunostaining The Journal of neuroscience Medium 29483282

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 The HtrA family of proteases: implications for protein composition and cell fate. Molecular cell 526 12408815
2011 HTRA proteases: regulated proteolysis in protein quality control. Nature reviews. Molecular cell biology 398 21326199
1997 The HtrA family of serine proteases. Molecular microbiology 318 9383148
2004 HtrA1 serine protease inhibits signaling mediated by Tgfbeta family proteins. Development (Cambridge, England) 282 14973287
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 178 15855271
2002 The HtrA1 serine protease is down-regulated during human melanoma progression and represses growth of metastatic melanoma cells. Oncogene 167 12242667
2005 Structure and function of HtrA family proteins, the key players in protein quality control. Journal of biochemistry and molecular biology 142 15943900
1996 Degradation by proteases Lon, Clp and HtrA, of Escherichia coli proteins aggregated in vivo by heat shock; HtrA protease action in vivo and in vitro. Molecular microbiology 123 8939438
2006 Serine protease HtrA1 modulates chemotherapy-induced cytotoxicity. The Journal of clinical investigation 122 16767218
2013 HtrA protease family as therapeutic targets. Current pharmaceutical design 121 23016688
2018 Extracellular HtrA serine proteases: An emerging new strategy in bacterial pathogenesis. Cellular microbiology 113 29582532
2009 HtrA serine proteases as potential therapeutic targets in cancer. Current cancer drug targets 112 19519315
2012 Architecture and regulation of HtrA-family proteins involved in protein quality control and stress response. Cellular and molecular life sciences : CMLS 106 22806565
2009 Serine protease HtrA1 associates with microtubules and inhibits cell migration. Molecular and cellular biology 96 19470753
2005 Role of HtrA in growth and competence of Streptococcus mutans UA159. Journal of bacteriology 93 15838029
2021 Serine Protease HTRA1 as a Novel Target Antigen in Primary Membranous Nephropathy. Journal of the American Society of Nephrology : JASN 91 33952630
2010 HtrA proteins as targets in therapy of cancer and other diseases. Expert opinion on therapeutic targets 90 20469960
2012 Structural and functional analysis of HtrA1 and its subdomains. Structure (London, England : 1993) 88 22578544
2018 HTRA1, an age-related macular degeneration protease, processes extracellular matrix proteins EFEMP1 and TSP1. Aging cell 85 29730901
2012 Human high temperature requirement serine protease A1 (HTRA1) degrades tau protein aggregates. The Journal of biological chemistry 81 22535953
2005 Role for HtrA in stress induction and virulence potential in Listeria monocytogenes. Applied and environmental microbiology 77 16085809
2020 HTRA1-Related Cerebral Small Vessel Disease: A Review of the Literature. Frontiers in neurology 76 32719647
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
2018 CADASIL brain vessels show a HTRA1 loss-of-function profile. Acta neuropathologica 71 29725820
2015 Characterisation of worldwide Helicobacter pylori strains reveals genetic conservation and essentiality of serine protease HtrA. Molecular microbiology 69 26568477
2010 C-reactive protein and CFH, ARMS2/HTRA1 gene variants are independently associated with risk of macular degeneration. Ophthalmology 63 20346514
2007 HtrA1 inhibits mineral deposition by osteoblasts: requirement for the protease and PDZ domains. The Journal of biological chemistry 61 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
2013 HtrA1 is induced by oxidative stress and enhances cell senescence through p38 MAPK pathway. Experimental eye research 59 23623979
2008 Changes in mRNA and protein levels of human HtrA1, HtrA2 and HtrA3 in ovarian cancer. Clinical biochemistry 55 18241672
2009 Expression of human HtrA1, HtrA2, HtrA3 and TGF-beta1 genes in primary endometrial cancer. Oncology reports 50 19424634
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 43 17635117
2018 Elevated HTRA1 and HTRA4 in severe preeclampsia and their roles in trophoblast functions. Molecular medicine reports 42 30015931
2010 The serine protease HtrA1 specifically interacts and degrades the tuberous sclerosis complex 2 protein. Molecular cancer research : MCR 42 20671064
2020 Campylobacter jejuni Serine Protease HtrA Cleaves the Tight Junction Component Claudin-8. Frontiers in cellular and infection microbiology 41 33364202
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
2017 Bacterial serine protease HtrA as a promising new target for antimicrobial therapy? Cell communication and signaling : CCS 39 28069057
2022 Exploring the contribution of ARMS2 and HTRA1 genetic risk factors in age-related macular degeneration. Progress in retinal and eye research 37 36581531
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
2006 Distinct expression and localization of serine protease HtrA1 in human endometrium and first-trimester placenta. Developmental dynamics : an official publication of the American Association of Anatomists 36 17072861
2018 Function of Serine Protease HtrA in the Lifecycle of the Foodborne Pathogen Campylobacter jejuni. European journal of microbiology & immunology 35 30345086
2013 HtrA1 in human urothelial bladder cancer: a secreted protein and a potential novel biomarker. International journal of cancer 35 23712470
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 HtrA1 in Gestational Diabetes Mellitus: A Possible Biomarker? Diagnostics (Basel, Switzerland) 34 36359548
2021 HTRA family proteins in pregnancy outcome. Tissue & cell 34 33915357
2017 Low HtrA1 expression in patients with long‑standing ulcerative colitis and colorectal cancer. Oncology reports 34 28586045
2001 HtrA protease and processing of extracellular proteins of Streptococcus mutans. FEMS microbiology letters 34 11682172
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
2008 Intracellular localization of the tumor suppressor HtrA1/Prss11 and its association with HPV16 E6 and E7 proteins. Journal of cellular biochemistry 33 18452160
2018 Inactivation of the serine protease HTRA1 inhibits tumor growth by deregulating angiogenesis. Oncogene 31 29713059
2014 The inhibitory effect of IFN-γ on protease HTRA1 expression in rheumatoid arthritis. Journal of immunology (Baltimore, Md. : 1950) 30 24907345
2023 Inhibiting HIF-1 signaling alleviates HTRA1-induced RPE senescence in retinal degeneration. Cell communication and signaling : CCS 29 37316948
2016 The function of the DegP (HtrA) protein: Protease versus chaperone. IUBMB life 29 27670951
1994 Cloning, characterization and construction of htrA and htrA-like mutants of Brucella abortus and their survival in BALB/c mice. Microbial pathogenesis 28 7861951
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
2017 HtrA1 activation is driven by an allosteric mechanism of inter-monomer communication. Scientific reports 25 29093542
2013 Variants at chromosome 10q26 locus and the expression of HTRA1 in the retina. Experimental eye research 25 23644223
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
2021 Ongoing controversies and recent insights of the ARMS2-HTRA1 locus in age-related macular degeneration. Experimental eye research 23 33930395
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 HtrA serine proteases in cancers: A target of interest for cancer therapy. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 22 34243596
2020 HTRA1-related autosomal dominant cerebral small vessel disease. Chinese medical journal 22 33109952
2018 BMP-Responsive Protease HtrA1 Is Differentially Expressed in Astrocytes and Regulates Astrocytic Development and Injury Response. The Journal of neuroscience : the official journal of the Society for Neuroscience 22 29483282
2017 High-Temperature Requirement A1 (Htra1) - A Novel Regulator of Canonical Wnt Signaling. Scientific reports 22 29269789
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
2024 HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species. Nature communications 21 38499535
2021 Overview of Human HtrA Family Proteases and Their Distinctive Physiological Roles and Unique Involvement in Diseases, Especially Cancer and Pregnancy Complications. International journal of molecular sciences 21 34639128
2021 Interplay between HTRA1 and classical signalling pathways in organogenesis and diseases. Saudi journal of biological sciences 21 35531175
2016 Epigenetic silencing of serine protease HTRA1 drives polyploidy. BMC cancer 21 27388476
2014 The HtrA-like protease CD3284 modulates virulence of Clostridium difficile. Infection and immunity 21 25047848
2019 Loss of the serine protease HTRA1 impairs smooth muscle cells maturation. Scientific reports 20 31796853
2021 Heterozygous HTRA1 nonsense or frameshift mutations are pathogenic. Brain : a journal of neurology 19 34270682
2015 HtrA1 resensitizes multidrug-resistant hepatocellular carcinoma cells by targeting XIAP. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 19 25776486
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
2021 Function, molecular mechanisms, and therapeutic potential of bacterial HtrA proteins: An evolving view. Computational and structural biotechnology journal 17 34976310
2020 RUNX2 co-operates with EGR1 to regulate osteogenic differentiation through Htra1 enhancers. Journal of cellular physiology 17 32324256
2023 HTRA1 in Placental Cell Models: A Possible Role in Preeclampsia. Current issues in molecular biology 16 37232715
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
2018 Heterozygous HTRA1 missense mutation in CADASIL-like family disease. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 15 29561953
2007 HtrA1 is a novel mast cell serine protease of mice and men. Molecular immunology 15 17292962
2024 Systematic Characterization of the Clinical and Pathological Features of Schwannomas Harboring SH3PXD2A::HTRA1 Fusion. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 14 38219951
2024 HTRA1 interacts with SLC7A11 to modulate colorectal cancer chemosensitivity by inhibiting ferroptosis. Cell death discovery 14 38740771
2022 Induction of IDO1 and Kynurenine by Serine Proteases Subtilisin, Prostate Specific Antigen, CD26 and HtrA: A New Form of Immunosuppression? Frontiers in immunology 14 35371018
2018 HtrA1 as a promising tissue marker in cancer: a meta-analysis. BMC cancer 14 29409460
2017 Biochemical properties of the HtrA homolog from bacterium Stenotrophomonas maltophilia. International journal of biological macromolecules 14 29155201
2015 HtrA1 regulates epithelial-mesenchymal transition in hepatocellular carcinoma. Biochemical and biophysical research communications 14 26403966
2014 Expression and localization of serine protease Htra1 in neuroblastoma: correlation with cellular differentiation grade. Journal of neuro-oncology 14 24493577
2017 SHAPE analysis of the htrA RNA thermometer from Salmonella enterica. RNA (New York, N.Y.) 13 28739676
2015 Serine protease HtrA1 as an inhibitor on proliferation invasion and migration of gastric cancer. Medical oncology (Northwood, London, England) 13 25761858

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