Characterization of human HtrA2, a novel serine protease involved in the mammalian cellular stress response
2000
Gray, Carol W. | Ward, Robin V. | Karran, Eric | Turconi, Sandra | Rowles, Alison | Viglienghi, Daniela | Southan, Christopher | Barton, Amanda | Fantom, Kenneth G. | West, Andrew | Savopoulos, John | Hassan, Namir J. | Clinkenbeard, Helen | Hanning, Charles | Amegadzie, Bernard | Davis, John B. | Dingwall, Colin | Livi, George P. | Creasy, Caretha L.
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 siteâdirected mutagenesis. In human cell lines, it is present as two polypeptides of 38 and 40âkDa. HumHtrA2 cleaves βâcasein with an inhibitor profile similar to that previously described for E.âcoli HtrA, in addition to an increase in βâcasein turnover when the assay temperature is raised from 37 to 45â°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.
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