DegS and YaeL participate sequentially in the cleavage of RseA to activate the ς^E-dependent extracytoplasmic stress response

Abstract

All cells have stress response pathways that maintain homeostasis in each cellular compartment. In the Gram-negative bacterium Escherichia coli, the E pathway responds to protein misfolding in the envelope. The stress signal is transduced across the inner membrane to the cytoplasm via the inner membrane protein RseA, the anti-sigma factor that inhibits the transcriptional activity of E . Stress-induced activation of the pathway requires the regulated proteolysis of RseA. In this report we show that RseA is degraded by sequential proteolytic events controlled by the inner membrane-anchored protease DegS and the membrane-embedded metalloprotease YaeL, an ortholog of mammalian Site-2 protease (S2P). This is consistent with the mechanism of activation of ATF6, the mammalian unfolded protein response transcription factor by Site-1 protease and S2P. Thus, mammalian and bacterial cells employ a conserved proteolytic mechanism to activate membrane-associated transcription factors that initiate intercompartmental cellular stress responses.

Structural basis for the negative regulation of bacterial stress response by RseB

“…1 In Gram-negative bacteria, the sequential cleavage of RseA, a membrane-spanning anti-rE factor, modulates the initiation of the envelope-stress response. 2,3 RseA forms a tight complex with rE using its N-terminal cytoplasmic domain, thereby inhibiting the transcription of rE-dependent genes. Under stress conditions that include the misfolding of periplasmic proteins, two membrane proteases, DegS and RseP, sequentially degrade RseA to liberate rE (Supporting Information Fig.…”

Unfolded protein responses in bacteria and mitochondria: A central role for the ClpXP machine

“…Thus, it appears that full activation of the envelope stress response requires two inducers one to activate DegS and another to inhibit RseB. Nevertheless, the cleavage of RseA by DegS is essential for the next step in the cascade, which is mediated by RseP (48,51,53).…”

“…2c). This action results in the release of the cytoplasmic domain of RseA (RseA ) from the membrane (48,51,58,59). Interestingly, the release of RseA 1-108 from the membrane is insufficient for SigmaE release or transcription of the SigmaE regulon (44,45).…”

“…2b). Once activated, DegS is able to cleave RseA, on the periplasmic side of its transmembrane domain (36,48,49,51,53). Another periplasmic sensor protein (RseB) is involved in the pathway, which interacts with, and inhibits the processing of RseA thereby dampening the signal transduction pathway (36,46,54,55).…”

“…2a). However, naturally there is a mechanism to release SigmaE, which occurs through a proteolytic cascade that focuses on the processing of RseA (36,45,(48)(49)(50)(51).…”