text: Streptococcus pyogenes has evolved an interwoven complex of gene regulatory mechanisms in the SIP signaling pathway by implanting a pH sensitive histidine switch onto the quorum-sensing ropB protein. During the neutral to basic pH conditions whether synthetically induced or naturally caused by low population density of S. pyogenes, the interaction between the unprotonated functionally involved histidine (H144) with relevant sidechains (Y176, Y182, E185) in the SIP binding pocket domain is impaired and speB protease expression is inhibited. On the other hand, as extracellular pH decreases to be more acidic in cases of high population density, S. pyogenes has no elaborate pH homeostatic capabilities relative to non-lactic bacteria, therefore intracellular cytosolic pH levels will more easily resemble extracellular levels. Cytosolic acidification mobilizes the SIP pathway to allow for the SIP-ropB protein complex to form and increasing SIP production. Furthermore, increased cytosolic acidity enhances the maturation of speB zymogen (speBz) into mature speB protease (speBm) to dramatically increase its proteolytic activity and virulence.