Regulated proteolysis: control of the Escherichia coli σ(E)-dependent cell envelope stress response.

Over the past decade, regulatory proteolysis has emerged as a paradigm for transmembrane signal transduction in all organisms, from bacteria to humans. These conserved proteolytic pathways share a common design that involves the sequential proteolysis of a membrane-bound regulatory protein by two proteases. Proteolysis releases the regulator, which is inactive in its membrane-bound form, into the cytoplasm where it performs its cellular function. One of the best-characterized examples of signal transduction via regulatory proteolysis is the pathway governing the σ(E)-dependent cell envelope stress response in Escherichia coli. In unstressed cells, σ(E) is sequestered at the membrane by the transmembrane anti-sigma factor, RseA. Stresses that compromise the cell envelope and interfere with the proper folding of outer membrane proteins (OMPs) activate the proteolytic pathway. The C-terminal residues of unfolded OMPs bind to the inner membrane protease, DegS, to initiate the proteolytic cascade. DegS removes the periplasmic domain of RseA creating a substrate for the next protease in the pathway, RseP. RseP cleaves RseA in the periplasmic region in a process called regulated intramembrane proteolysis (RIP). The remaining fragment of RseA is released into the cytoplasm and fully degraded by the ATP-dependent protease, ClpXP, with the assistance of the adaptor protein, SspB, thereby freeing σ(E) to reprogram gene expression. A growing body of evidence indicates that the overall proteolytic framework that governs the σ(E) response is used to regulate similar anti-sigma factor/sigma factor pairs throughout the bacterial world and has been adapted to recognize a wide variety of signals and control systems as diverse as envelope stress responses, sporulation, virulence, and iron-siderophore uptake. In this chapter, we review the extensive physiological, biochemical, and structural studies on the σ(E) system that provide remarkable insights into the mechanistic underpinnings of this regulated proteolytic signal transduction pathway. These studies reveal design principles that are applicable to related proteases and regulatory proteolytic pathways in all domains of life.