Characterization of human HtrA2, a novel serine protease involved in the mammalian cellular stress response

C W Gray, R V Ward, E Karran, S Turconi, A Rowles, D Viglienghi, C Southan, A Barton, K G Fantom, A West, J Savopoulos, N J Hassan, H Clinkenbeard, C Hanning, B Amegadzie, J B Davis, C Dingwall, G P Livi, C L Creasy

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Human HtrA2 is a novel member of the HtrA serine protease family and shows extensive homology to the Escherichia coli HtrA genes that are essential for bacterial survival at high temperatures. HumHtrA2 is also homologous to human HtrA1, also known as L56/HtrA, which is differentially expressed in human osteoarthritic cartilage and after SV40 transformation of human fibroblasts. HumHtrA2 is upregulated in mammalian cells in response to stress induced by both heat shock and tunicamycin treatment. Biochemical characterization of humHtrA2 shows it to be predominantly a nuclear protease which undergoes autoproteolysis. This proteolysis is abolished when the predicted active site serine residue is altered to alanine by site-directed mutagenesis. In human cell lines, it is present as two polypeptides of 38 and 40 kDa. HumHtrA2 cleaves beta-casein with an inhibitor profile similar to that previously described for E. coli HtrA, in addition to an increase in beta-casein turnover when the assay temperature is raised from 37 to 45 degrees C. The biochemical and sequence similarities between humHtrA2 and its bacterial homologues, in conjunction with its nuclear location and upregulation in response to tunicamycin and heat shock suggest that it is involved in mammalian stress response pathways.

Original languageEnglish
Pages (from-to)5699-710
Number of pages12
JournalEuropean Journal of Biochemistry
Issue number18
Publication statusPublished - Sept 2000

Keywords / Materials (for Non-textual outputs)

  • Alanine
  • Amino Acid Sequence
  • Animals
  • Anti-Bacterial Agents
  • Base Sequence
  • Binding Sites
  • Blotting, Northern
  • Blotting, Western
  • COS Cells
  • Carrier Proteins
  • Caseins
  • Cell Line
  • Cell Nucleus
  • Chromatography, High Pressure Liquid
  • Cloning, Molecular
  • Endoplasmic Reticulum
  • Escherichia coli
  • Fibroblasts
  • Heat-Shock Proteins
  • Hot Temperature
  • Humans
  • Membrane Proteins
  • Mice
  • Microscopy, Fluorescence
  • Mitochondrial Proteins
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Periplasmic Proteins
  • Presenilin-1
  • Proto-Oncogene Proteins c-jun
  • RNA, Messenger
  • Recombinant Proteins
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Homology, Amino Acid
  • Serine
  • Serine Endopeptidases
  • Subcellular Fractions
  • Temperature
  • Time Factors
  • Tissue Distribution
  • Tunicamycin
  • Two-Hybrid System Techniques
  • Up-Regulation


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