HtrA

HtrA, short for high-temperature requirement A, is a family of serine proteases characterized by a conserved N-terminal protease domain and one or more C-terminal PDZ domains. The family is found in bacteria and eukaryotes and is known for dual functionality as proteases and molecular chaperones that assist in protein quality control, especially under stress conditions. In bacteria, members are typically periplasmic; in metazoans, they can be mitochondrial or secreted.

In Gram-negative bacteria, DegP (HtrA), DegQ and DegS are core members. DegP and DegQ function as periplasmic proteases and chaperones that refold or degrade misfolded proteins during heat shock. DegS is a sensor protease that initiates the envelope stress response by cleaving the anti-sigma factor RseA in response to misfolded outer membrane proteins, releasing the sigmaE transcription factor. These proteins often form oligomers whose assembly regulates proteolysis; some HtrA proteases from pathogens are secreted and contribute to virulence by targeting host proteins.

Human and other metazoan HtrA family members include HTRA1, HTRA2/Omi, and HTRA3. HTRA1 is secreted or extracellular; HTRA2/Omi is mitochondrial. Both are serine proteases with PDZ domains that regulate substrate recognition. Mutations in HTRA1 cause CARASIL, a hereditary cerebral small-vessel arteriopathy. HTRA2/Omi has been studied for roles in apoptosis and neurodegeneration, including Parkinson’s disease research. Dysregulation of HtrA activity has been linked to cancer and inflammatory conditions, and inhibitors or activators are under investigation as potential therapies.

HtrA proteins thus play a conserved role in protein homeostasis across domains of life, balancing chaperone and proteolytic activities in response to cellular stress and contributing to development and disease through diverse substrates and regulatory interactions.