HtrA Protease Family as Therapeutic Targets

Abstract

The HtrA proteases degrade damaged proteins and thus control the quality of proteins and protect cells against the consequences of various stresses; they also recognize specific protein substrates and in this way participate in regulation of many pathways. In many pathogenic bacteria strains lacking the HtrA function lose virulence or their virulence is decreased. This is due to an increased vulnerability of bacteria to stresses or to a decrease in secretion of virulence factors. In some cases HtrA is secreted outside the cell, where it promotes the pathogen's invasiveness. Thus, the HtrA proteases of bacterial pathogens are attractive targets for new therapeutic approaches aimed at inhibiting their proteolytic activity. The exported HtrAs are considered as especially promising targets for chemical inhibitors. In this review, we characterize the model prokaryotic HtrAs and HtrAs of pathogenic bacteria, focusing on their role in virulence. In humans HtrA1, HtrA2(Omi) and HtrA3 are best characterized. We describe their role in promoting cell death in stress conditions and present evidence indicating that HtrA1 and HtrA2 function as tumor suppressors, while HtrA2 stimulates cancer cell death induced by chemotherapeutic agents. We characterize the HtrA2 involvement in pathogenesis of Parkinson's and Alzheimer's diseases, and briefly describe the involvement of human HtrAs in other diseases. We hypothesize that stimulation of the HtrA's proteolytic activity might be beneficial in therapies of cancer and neurodegenerative disorders, and discuss the possibilities of modulating HtrA proteolytic activity considering the present knowledge about their structure and regulation.

The LA Loop as an Important Regulatory Element of the HtrA (DegP) Protease from Escherichia coli

“…The plasmids pJS13 or pJS14, pJSFW, or pJS19 were used as templates to generate the pDF plasmids (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) or the pMD2, pJSFW, and the pDF 21A, pDF19A, or pDF (20A, 22A) plasmid, respectively. The oligonucleotide primers used for mutagenesis were designed according to the QuikChange mutagenesis kit protocol and are listed in supplemental Table S2.…”

“…DegS from Escherichia coli up-regulates the 24 transcription factor by degradation of the anti-factor RseA (for review, see Ref. 1). All such functions may affect the virulence of pathogenic bacteria either directly or indirectly.…”

Transcriptomic analysis of mouse limb tendon cells during development

“…However, AQP1 function in tendon development is not yet known. The serine protease gene Htra3, which is known to act as a tumour suppressor (Skorko-Glonek et al, 2013), has until now never been associated with tendon formation. Lastly, among the top enriched genes, we found components of the TGF-β pathway, including the thrombospondin genes Thbs2 and Thbs4, which were expressed in mouse limb tendons.…”

Substrate Specificity of MarP, a Periplasmic Protease Required for Resistance to Acid and Oxidative Stress in Mycobacterium tuberculosis

“…HtrA-family proteases are periplasmic serine proteases characterized by at least one C-terminal PDZ protein-protein interaction domain and an association with the cytoplasmic membrane (25,26). They function as both proteases and oligomeric chaperones depending on the molecular signal (27).…”