A phosphohistidine phosphatase promotes starvation survival by dephosphorylating nucleoside diphosphate kinase

Nucleoside diphosphate kinase (Ndk) is a ubiquitous enzyme that maintains the cellular nucleoside triphosphate (NTP) pool and participates in many other pathways of eukaryotes and prokaryotes. Here, we show that in Escherichia coli, Ndk is regulated by dephosphorylation of its phosphohistidine intermediate via the phosphatase SixA, thereby inhibiting nucleotide phosphoryl transfer activity. We further show that loss of this regulation alters the metabolic state of E. coli in low-nutrient conditions and reduces survival in long-term stationary phase. Similar regulation of Ndk by a phosphohistidine phosphatase has been reported previously for human cells, although the molecular interactions differ. The prevalence of SixA and Ndk orthologs in prokaryotes and the appearance of this regulatory mechanism in both E. coli and humans suggest that phosphohistidine phosphatase-mediated control of nucleoside diphosphate kinases may be widespread.