The enigmatic Rid7C protein is an endoribonuclease involved in the differentiation and production of the glycopeptide antibiotic A40926 in Nonomuraea gerenzanensis

The protein family YjgF/YER057c/UK114 (Rid) is widespread in all domains of life. The only member of this superfamily biochemically well-characterized is the archetypal RidA that is involved in detoxification. Besides RidA, seven families named Rid1 to Rid7 are identified in prokaryotes. A conserved arginine residue is shared by all Rid members with the detoxifying activity. Conversely, other members lack the arginine residue, and their role is mysterious.

A step toward understanding the role of these proteins has been achieved by studying a protein, called Rid7C, in Nonomuraea gerenzanensis, a rare actinomycete used to produce the A40926, which is the precursor of dalbavancin, an FDA approved antibiotic effective against Staphylococcus aureus MRSA. This actinomycete is characterized by the presence of duplicated genes encoding β-subunit of RNA polymerase: rpoB(S) (wild-type gene) and rpoB(R) (specialist rpoB gene). RpoB(R) isoform controls the morphological differentiation and the activation of secondary metabolism (including the production of A40926). Translation of the RpoB(R) mRNA is negatively modulated by a self-complementary hairpin loop in its 5’-UTR which hides the Shine & Dalgarno sequence. Rid7C is the endoribonuclease involved in resolving the hairpin loop by removing a ~80 nt segment from the rpoB(R) mRNA end. In addition, Rid7C may be associated with ribonuclease P M1 RNA, although M1 RNA is not required for rpoB(R) mRNA processing in vitro. Computational, in vitro and in vivo evidence suggest that Rid7C endoribonuclease activity is inhibited by A40926 suggesting the existence of a negative feedback loop on A40926 production, and a role of the A40926 in the modulation of differentiation in this microorganism. This new molecular tool, namely the co-overexpression of RpoB (R) and Rid7C, can be used to increase antibiotic production in actinomycetes. Computational modelling suggests that Rid7 proteins may be involved in the molecular mechanisms of infections in pathogens, so these proteins could be a new target for innovative anti-infective agents.