Pseudomonas aeruginosa is a Gram-negative opportunistic human pathogen and a threat for immunocompromised and cystic
fibrosis patients. It is responsible for acute and chronic infections and can switch between these lifestyles upon taking an informed
decision involving complex regulatory networks. The RetS/LadS/Gac/Rsm network and the cyclic-di-GMP (c-di-GMP)
signaling pathways are both central to this phenomenon redirecting the P. aeruginosa population toward a biofilm mode of
growth, which is associated with chronic infections. While these two pathways were traditionally studied independently from
each other, we recently showed that cellular levels of c-di-GMP are increased in the hyperbiofilm retS mutant. Here, we have formally
established the link between the two networks by showing that the SadC diguanylate cyclase is central to the Gac/Rsmassociated
phenotypes, notably, biofilm formation. Importantly, SadC is involved in the signaling that converges onto the RsmA
translational repressor either via RetS/LadS or via HptB/HsbR. Although the level of expression of the sadC gene does not seem
to be impacted by the regulatory cascade, the production of the SadC protein is tightly repressed by RsmA. This adds to the
growing complexity of the signaling network associated with c-di-GMP in P. aeruginosa. While this organism possesses more
than 40 c-di-GMP-related enzymes, it remains unclear how signaling specificity is maintained within the c-di-GMP network. The
finding that SadC but no other diguanylate cyclase is related to the formation of biofilm governed by the Gac/Rsm pathway further
contributes to understanding of this insulation mechanism.