38A bacterium's ability to thrive in the presence of multiple environmental stressors 39 simultaneously determines its resilience. We showed that activation of the SigB-40 controlled general stress response by mild environmental or nutritional stress provided 41 significant cross-protection to subsequent lethal oxidative, disulfide and nitrosative 42 stress exposure. SigB activation is mediated via the stressosome and RsbP, the main 43 conduits of environmental and nutritional stress, respectively. Cells exposed to mild 44 environmental stress while lacking the major stressosome components RsbT or RsbRA 45were highly sensitive to subsequent oxidative stress, whereas rsbRB, rsbRC, rsbRD 46 and ytvA null mutants showed a spectrum of sensitivity, confirming their redundant roles 47 Interestingly, optimum cross-protection against nitrosative stress caused by SNP 53 required SigB but not the known regulators, RsbT and RsbP, suggesting an additional 54and as yet uncharacterized route of SigB activation independent of the known 55 environmental and energy-stress pathways. Together, these results provide a 56 mechanism for how Bacillus subtilis promotes enhanced resistance against lethal 57 oxidative stress during likely physiologically relevant conditions such as mild 58 environmental or nutrient stress. 59
Importance 60The Bacillus subtilis general stress response is a model for gram-positive pathogens 61 because the regulators are conserved, and the Sigma factor, SigB, controls expression 62 of virulence genes in Listeria monocytogenes. We showed that B. subtilis SigB 63 promotes survival to oxidative, disulfide and nitrosative stress through priming or cross-64 protection. Moreover, when cells were exposed to nitrosative stress, priming was SigB 65dependent, yet the known regulators of SigB were not required, suggesting an 66 alternative mode of SigB activation during nitrosative stress. Importantly, we showed the 67 first genetic requirements of stressosome genes, rsbRB and rsbRD, during oxidative 68 stress cross-protection not explained by environmental stress activation, suggesting a 69 role for stressosome proteins during oxidative stress and advancing the role of SigB 70 during antioxidant protection. 71 72 73