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Gene Review

HTRA1  -  HtrA serine peptidase 1

Homo sapiens

Synonyms: ARMD7, CARASIL, HTRA, High-temperature requirement A serine peptidase 1, HtrA, ...
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Disease relevance of HTRA1


Psychiatry related information on HTRA1


High impact information on HTRA1

  • The accumulation of misfolded porins in the periplasm of bacteria triggers a proteolytic cascade, initiated by activation of DegS, a member of the family of HtrA proteases [6].
  • One quality control factor is HtrA, one of a new class of oligomeric serine proteases [7].
  • The defining feature of the HtrA family is the combination of a catalytic domain with at least one C-terminal PDZ domain [7].
  • These results suggest that the activation of the proteolytic function of HtrA at elevated temperatures might occur by a conformational change, which includes the opening of the helical lid to expose the active site and subsequent rearrangement of a catalytic triad and an oxyanion hole [8].
  • These changes did not appear to be because of alterations in protein folding induced by mutagenesis, because the IGFBP-5 mutant was fully susceptible to proteolytic cleavage by a specific IGFBP-5 protease [9].

Biological context of HTRA1


Anatomical context of HTRA1

  • Preliminary analysis of lymphocytes and retinal pigment epithelium from four AMD patients revealed that the risk allele was associated with elevated expression levels of HTRA1 mRNA and protein [1].
  • Stable PRSS11 overexpression in the metastatic cell line strongly inhibited proliferation, chemoinvasion and Nm23-H1 protein expression in vitro, as well as cell growth in vivo in nu/nu mice [3].
  • In bacteria, the chief role of HtrA is recognition and degradation of misfolded proteins in the periplasm, combining a dual activity of chaperone and protease [4].
  • Here we characterize an L. pneumophila mutant defective in the HtrA/DegP stress-induced protease/chaperone homologue and show that HtrA is indispensable for intracellular replication within mammalian macrophages and alveolar epithelial cells and for intrapulmonary replication in A/J mice [12].
  • Because the IGFBP-5 protease activity that is secreted by fibroblasts has been shown to be due to the complement components C1r and C1s, these studies were undertaken to determine whether smooth muscle cells also secreted these proteases and to identify some of the factors that regulate their secretion by both cell types [13].

Associations of HTRA1 with chemical compounds

  • The HTRA1 gene encodes a secreted serine protease [1].
  • The IGFBP-5 protease activity was inhibited by EDTA, phenanthroline and PMSF [14].
  • To determine the physiological significance of this increase in C1r and C1s, the amount of IGFBP-5 protease activity that was present in conditioned medium was determined before and after exposure to TNFalpha, IL-beta, and dexamethasone [13].
  • Here we show that the IGFBP-5 protease present in bovine follicular fluid is a neutral/basic pH-favoring, Zn(2+) metalloprotease very similar to the previously described IGFBP-4 protease [15].
  • While lack of HtrA reduces the oxygen tolerance of C. jejuni, the htrA mutant was not sensitive to compounds that increase the formation of oxygen radicals, such as paraquat, cumene hydroperoxide, and H2O2 [16].

Other interactions of HTRA1

  • HTRA3 is a newly identified serine peptidase of the mammalian HTRA (high-temperature requirement factor A) family, that is upregulated dramatically during mouse placental development [17].
  • The human HtrA family of proteases consists of three members: HtrA1, HtrA2, and HtrA3 [4].
  • The proteolytic activity against IGFBP-6 differed at least from IGFBP-5 protease activity in its sensitivity both to IGF-II and to the hydroxamic acid-based disintegrin metalloprotease inhibitor, as well as serine protease inhibitors [18].
  • ADAM12 (A disintegrin and metalloprotease) is an IGFBP-3 and IGFBP-5 protease and is present in human pregnancy serum [19].
  • Additionally, a classifier, including PRSS11, MTSS1, and CLPTM1, could correctly distinguish 95.4% of the 44 samples analyzed, with only two misclassifications, one sensitive sample and one resistant tumor [20].

Analytical, diagnostic and therapeutic context of HTRA1

  • DNA extracted from all Brucella species, reference and vaccine strains were amplified by PCR using primers specific for the genes encoding a 31-kDa Brucella protein, the heat shock proteins (DnaJ, DnaK, HtrA and GroEL) and 16S RNA [21].


  1. A Variant of the HTRA1 Gene Increases Susceptibility to Age-Related Macular Degeneration. Yang, Z., Camp, N.J., Sun, H., Tong, Z., Gibbs, D., Cameron, D.J., Chen, H., Zhao, Y., Pearson, E., Li, X., Chien, J., Dewan, A., Harmon, J., Bernstein, P.S., Shridhar, V., Zabriskie, N.A., Hoh, J., Howes, K., Zhang, K. Science (2006) [Pubmed]
  2. Human HtrA, an evolutionarily conserved serine protease identified as a differentially expressed gene product in osteoarthritic cartilage. Hu, S.I., Carozza, M., Klein, M., Nantermet, P., Luk, D., Crowl, R.M. J. Biol. Chem. (1998) [Pubmed]
  3. The HtrA1 serine protease is down-regulated during human melanoma progression and represses growth of metastatic melanoma cells. Baldi, A., De Luca, A., Morini, M., Battista, T., Felsani, A., Baldi, F., Catricalà, C., Amantea, A., Noonan, D.M., Albini, A., Natali, P.G., Lombardi, D., Paggi, M.G. Oncogene (2002) [Pubmed]
  4. Distribution of the serine protease HtrA1 in normal human tissues. De Luca, A., De Falco, M., Severino, A., Campioni, M., Santini, D., Baldi, F., Paggi, M.G., Baldi, A. J. Histochem. Cytochem. (2003) [Pubmed]
  5. Three SNPs in the GSTO1, GSTO2 and PRSS11 genes on chromosome 10 are not associated with age-at-onset of Alzheimer's disease. Ozturk, A., Desai, P.P., Minster, R.L., Dekosky, S.T., Kamboh, M.I. Neurobiol. Aging (2005) [Pubmed]
  6. A PDZ switch for a cellular stress response. Schlieker, C., Mogk, A., Bukau, B. Cell (2004) [Pubmed]
  7. The HtrA family of proteases: implications for protein composition and cell fate. Clausen, T., Southan, C., Ehrmann, M. Mol. Cell (2002) [Pubmed]
  8. Crystal structure of the protease domain of a heat-shock protein HtrA from Thermotoga maritima. Kim, D.Y., Kim, D.R., Ha, S.C., Lokanath, N.K., Lee, C.J., Hwang, H.Y., Kim, K.K. J. Biol. Chem. (2003) [Pubmed]
  9. Substitutions for hydrophobic amino acids in the N-terminal domains of IGFBP-3 and -5 markedly reduce IGF-I binding and alter their biologic actions. Imai, Y., Moralez, A., Andag, U., Clarke, J.B., Busby, W.H., Clemmons, D.R. J. Biol. Chem. (2000) [Pubmed]
  10. HTRA1 Promoter Polymorphism in Wet Age-Related Macular Degeneration. Dewan, A., Liu, M., Hartman, S., Zhang, S.S., Liu, D.T., Zhao, C., Tam, P.O., Chan, W.M., Lam, D.S., Snyder, M., Barnstable, C., Pang, C.P., Hoh, J. Science (2006) [Pubmed]
  11. Localization of the gene for a serine protease with IGF-binding domain (PRSS11) to human chromosome 10q25.3-q26.2. Zumbrunn, J., Trueb, B. Genomics (1997) [Pubmed]
  12. HtrA homologue of Legionella pneumophila: an indispensable element for intracellular infection of mammalian but not protozoan cells. Pedersen, L.L., Radulic, M., Doric, M., Abu Kwaik, Y. Infect. Immun. (2001) [Pubmed]
  13. Control of insulin-like growth factor binding protein-5 protease synthesis and secretion by human fibroblasts and porcine aortic smooth muscle cells. Moralez, A., Busby, W.H., Clemmons, D. Endocrinology (2003) [Pubmed]
  14. Proteolysis of insulin-like growth factor binding protein-5 by pregnancy serum and amniotic fluid. Claussen, M., Zapf, J., Braulke, T. Endocrinology (1994) [Pubmed]
  15. Selection of the dominant follicle and insulin-like growth factor (IGF)-binding proteins: evidence that pregnancy-associated plasma protein A contributes to proteolysis of IGF-binding protein 5 in bovine follicular fluid. Rivera, G.M., Fortune, J.E. Endocrinology (2003) [Pubmed]
  16. The HtrA protease of Campylobacter jejuni is required for heat and oxygen tolerance and for optimal interaction with human epithelial cells. Brøndsted, L., Andersen, M.T., Parker, M., Jørgensen, K., Ingmer, H. Appl. Environ. Microbiol. (2005) [Pubmed]
  17. Serine peptidase HTRA3 is closely associated with human placental development and is elevated in pregnancy serum. Nie, G., Li, Y., Hale, K., Okada, H., Manuelpillai, U., Wallace, E.M., Salamonsen, L.A. Biol. Reprod. (2006) [Pubmed]
  18. MDCK cells secrete neutral proteases cleaving insulin-like growth factor-binding protein-2 to -6. Shalamanova, L., Kübler, B., Scharf, J.G., Braulke, T. Am. J. Physiol. Endocrinol. Metab. (2001) [Pubmed]
  19. ADAM12: a novel first-trimester maternal serum marker for Down syndrome. Laigaard, J., Sørensen, T., Fröhlich, C., Pedersen, B.N., Christiansen, M., Schiøtt, K., Uldbjerg, N., Albrechtsen, R., Clausen, H.V., Ottesen, B., Wewer, U.M. Prenat. Diagn. (2003) [Pubmed]
  20. Gene expression profile associated with response to doxorubicin-based therapy in breast cancer. Folgueira, M.A., Carraro, D.M., Brentani, H., Patrão, D.F., Barbosa, E.M., Netto, M.M., Caldeira, J.R., Katayama, M.L., Soares, F.A., Oliveira, C.T., Reis, L.F., Kaiano, J.H., Camargo, L.P., Vêncio, R.Z., Snitcovsky, I.M., Makdissi, F.B., e Silva, P.J., Góes, J.C., Brentani, M.M. Clin. Cancer Res. (2005) [Pubmed]
  21. Specificity of six gene sequences for the detection of the genus Brucella by DNA amplification. Da Costa, M., Guillou, J.P., Garin-Bastuji, B., Thiébaud, M., Dubray, G. J. Appl. Bacteriol. (1996) [Pubmed]
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