DEGs

DegS is a periplasmic serine protease of the HtrA family in Gram-negative bacteria. It is anchored to the inner membrane by an N-terminal transmembrane helix, with a periplasmic serine protease domain followed by a C-terminal PDZ domain. DegS acts as the initial protease in the sigmaE (σE) envelope stress response by proteolytically cleaving the anti-sigma factor RseA in the periplasm when misfolded outer membrane proteins accumulate in the cell envelope. This proteolysis releases the sigmaE factor from RseA, enabling it to associate with RNA polymerase and drive transcription of stress response genes, including those involved in outer membrane biogenesis and protein folding.

Activation of DegS is allosterically regulated by peptide signals that bind the PDZ domain. The binding of C-terminal peptides derived from misfolded outer membrane proteins relieves autoinhibition and stimulates DegS proteolytic activity. After RseA is first cleaved by DegS, the remaining periplasmic fragment is further processed by an intramembrane protease, RseP (YaeL), within the membrane, releasing active sigmaE into the cytoplasm. The sigmaE regulon then coordinates a broad response to envelope stress.

DegS is widely distributed among Gram-negative bacteria and is considered essential for maintaining envelope integrity under stress. Mutations affecting DegS activity can alter sensitivity to stress and impact virulence in some pathogens. As a member of the HtrA family, DegS shares features with other periplasmic proteases, including a catalytic serine residue and a PDZ domain that regulates activity.