Inhibitor of intramembrane protease RseP blocks the σ ^E response causing lethal accumulation of unfolded outer membrane proteins

Abstract

Significance The σ E stress response monitors outer membrane protein (OMP) assembly. Uninduced, σ E is sequestered to the plasma membrane by its anti-sigma factor, RseA. Mutations perturbing OMP biogenesis induce degradation of RseA by the proteases DegS and RseP, liberating σ E so it can activate gene expression. σ E activity is essential in wild-type Escherichia coli , although why it is essential has remained unclear. We report that batimastat is an inhibitor of RseP, preventing it from cleaving RseA and thereby causing a lethal decrease in σ E activity. Surprisingly, lethality is caused by the accumulation of unfolded OMPs, despite a wild-type OMP biogenesis pathway. Hence, σ E is essential because it must fine-tune OMP synthesis, assembly, and degradation to prevent the appearance of toxic unfolded OMPs.