Lysine propionylation modulates the transcriptional activity of phosphate regulator PhoP in Saccharopolyspora erythraea.

Phosphate concentration extensively modulates the central physiological processes mediated by the two-component system PhoR-PhoP in actinobacteria. The system serves a role beyond phosphate metabolism, mediating crucial functions in nitrogen and carbon metabolism, and secondary metabolism in response to the nutritional states. Here, we found that the phosphate-sensing regulator PhoP was propionylated, and thus lost its DNA-binding activity in vivo and in vitro in Saccharopolyspora erythraea. Two key conserved lysine residues 198 and 203 (K198 and K203) in winged HTH motif at the C-terminal domain of PhoP are propionylated by protein acyltransferase AcuA (encoding by sace_5148). Single amino acid mutation of these two lysine residues resulted in severely impaired binding of PhoP to PHO box. The addition of propionate (to supply precursors for erythromycin biosynthesis) increases the intracellular propionylation level of PhoP, resulting in the loss of response to phosphate availability. Furthermore, simultaneous mutation of K198 and K203 of PhoP to arginine, mimicking the non-propionylated form, promotes the expression of the PhoP regulon under the condition of propionate addition. Together, these findings present a common regulatory mechanism of genes' expression mediated by posttranslational regulation of OmpR family transcriptional regulator PhoP and provide new insights into the multifaceted regulation of metabolism in response to nutritional signals.