In Escherichia coli, adaptation to extra-cytoplasmic stress relies on sigma(E) activation to induce a rescue pathway. Under non-stressed conditions, sigma(E) is sequestered by the inner membrane protein RseA. Extra-cytoplasmic stress activates DegS-dependent cleavage of RseA, rendering RseA sensitive to further degradation by the YaeL protease. YaeL contains two motifs characteristic of a family of metallo-proteases, as well as a periplasmic PDZ domain. We report results of mutational analyses of the YaeL domains. Surprisingly, expression in a strain depleted for wild-type YaeL or YaeL variants having a 40 amino acid deletion of the PDZ domain or amino acid substitutions of conserved amino acids of the YaeL PDZ domain did not affect cell viability. The proteolytic activity against RseA of these YaeL variants became independent of DegS. These observations suggest that the YaeL PDZ domain exerts a negative control on YaeL activity. Rather than being involved in substrate recognition, the PDZ domain of YaeL is likely to act as an inhibitor of proteolytic activity.