Serine protease HtrA (HtrA)

Serine protease HtrA (High temperature requirement A) is a critical virulence factor and essential protein produced by the bacterium Helicobacter pylori (UniProt O25663). It functions as both a molecular chaperone in the periplasm, ensuring proper protein folding under stress, and as a secreted serine protease in the extracellular environment (NIH, PMID: 38231222). In the gastric mucosa, HtrA specifically targets and cleaves the extracellular domain of the host cell-adhesion protein E-cadherin, as well as other junctional proteins like claudin-8 and occludin (EMBO Rep, 2010). This proteolytic activity leads to the disruption of adherens and tight junctions, compromising the integrity of the gastric epithelial barrier and allowing H. pylori to invade the paracellular space (NIH, PMID: 27551158). Furthermore, HtrA-mediated cleavage of E-cadherin facilitates the translocation of other bacterial effectors, such as the oncoprotein CagA, into host cells (NIH, PMID: 21455477). Due to its dual role in bacterial physiology and host pathogenesis, HtrA is a high-priority target for the development of novel anti-infective agents aimed at treating H. pylori infections and preventing associated diseases like peptic ulcers and gastric cancer (NIH, PMID: 23433388). Experimental inhibitors like JO146 and various small molecules found through virtual screening have shown potential in blocking HtrA activity and bacterial invasion (PLoS ONE, 2011). However, achieving selectivity over human HtrA homologs remains a significant therapeutic challenge (NIH, PMID: 30144448).

Other names

High temperature requirement AHtrAHpHP1019DegPHelicobacter pylori extracellular protease

Inhibition of the serine protease activity of HtrA, preventing the cleavage of host E-cadherin and disrupting bacterial protein quality control, which leads to reduced bacterial survival and virulence.