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

service Email alerting click here top right corner of the article or Receive free email alerts when new articles cite this article-sign up in the box at the 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. Stress response pathways that sense protein misfolding and other cellular damage in one compartment of the cell and transduce this signal to another cellular compartment are essential for balanced cell growth. Eukary-otic cells sense protein misfolding in the endoplasmic reticulum (ER) and transduce this signal to the nucleus of the cell to generate an appropriate response. This process has been called the unfolded protein response (UPR) (for review, see Patil and Walter 2001). Likewise, Gram-negative bacteria sense unfolded proteins in the envelope compartment of the cell and transduce this signal to the cytoplasmic compartment to generate a response. This process has been termed the extracytoplasmic stress response. In this report, we show that the ␴ E-dependent Escherichia coli extracytoplasmic stress response has a proteolytic regulatory element that is similar to that of the ATF6-dependent response of mammalian cells during the UPR (Ye et al. 2000) and the sterol regulatory element-binding protein (SREBP)-dependent response to sterol deprivation (Brown et al. 2000). In mammals, the UPR is initiated in part by the processing of ATF6, an integral membrane protein with an N-terminal, cytoplasmic basic leucine zipper (bZIP) transcription factor domain (Haze et al. 1999). The C-terminal domain of ATF6 projects into the ER and is positioned to sense stress in that cellular compartment (Haze et al. 1999). During ER stress, the bZIP domain is released by sequential proteolytic events …