The single-domain response regulator LerC functions as a connector protein in the Legionella pneumophila effectors regulatory network.

The intracellular pathogen Legionella pneumophila translocates more than 300 effector proteins into host cells during infection. The PmrAB two-component system (TCS) has been shown to activate the expression of a large pool of these effector-encoding genes (EEGs) and the LetAS TCS, as part of the LetAS-RsmYZ-CsrA cascade, has been shown to repress the expression of another pool of EEGs. We identified a single-domain response regulator (SDRR), named LerC, which functions as a connector protein between the PmrAB and the LetAS TCSs. The lerC gene is strongly activated by the PmrAB TCS and the LerC protein inhibits the activity of the LetAS TCS. The LerC protein specifically interacts with the HPT (histidine-phosphotransfer) domain of LetS, leading to reduced expression of the small RNAs RsmY and RsmZ, which leads to a reduced expression of the pool of EEGs regulated by the LetAS-RsmYZ-CsrA cascade. In addition, the conserved aspartic acid located in the LerC receiver domain is essential for its phosphorylation and function, suggesting that LerC functions as a phosphate-sink of LetS. Our results demonstrate a new role for SDRRs as connector proteins in regulatory networks, suggesting that members of this widespread group of proteins might function as connector proteins in other bacterial regulatory networks.