Role of stoichiometry and implicit negative feedback in sigma factor regulation

Despite the central role of alternative sigma factors in bacterial stress response and virulence their regulation remains poorly understood. Here we investigate one of best-studied examples of alternative sigma factors: the σB network that controls the general stress response of Bacillus subtilis to uncover widely relevant general design principles that describe the structure-function relationship of alternative sigma factor regulatory networks. We show that the relative stoichiometry of the synthesis rates of σB, its anti-sigma factor RsbW and the anti-anti-sigma factor RsbV, plays a critical role in shaping the network behavior by forcing the σB network to function as an ultrasensitive negative feedback loop. We further demonstrate how this type of negative feedback regulation insulates alternative sigma factor activity from competition with the housekeeping sigma factor for RNA polymerase and allows multiple stress sigma factors to function simultaneously with little competitive interference.