A single amino acid of a Salmonella virulence protein contributes to pathogenicity by protecting from the FtsH-mediated proteolysis

• Trp226 of the Salmonella MgtC protein is conserved only in intracellular pathogens.
• Trp226 to Ala substitution promotes MgtC degradation by the FtsH protease.
• Salmonella MgtC Trp226 protects from proteolysis, promoting virulence.
• The FtsH protease is inactive inside host, further increasing the MgtC protein.

FtsH is a membrane-bound ATP-dependent protease in bacteria that is critical for degrading membrane proteins. The MgtC virulence protein from Salmonella enterica is located at the inner membrane and required for survival inside macrophages. Here we report that a single substitution at tryptophan 226 of the MgtC protein to alanine promotes the FtsH-mediated proteolysis. The Trp residue is located at the very C-terminus of the cytoplasmic domain of the MgtC protein and conserved only in intracellular pathogens surviving within a macrophage phagosome, suggesting that Salmonella may acquire the tryptophan residue to prevent MgtC degradation by the FtsH protease. Moreover, the reduced proteolytic activity of the FtsH protease during infection further increases MgtC production, promoting Salmonella’s pathogenicity inside phagocytic cells.