# A phosphohistidine phosphatase promotes starvation survival by dephosphorylating nucleoside diphosphate kinase

## TL;DR

A phosphatase enzyme helps bacteria survive starvation by deactivating a key nucleotide enzyme.

## Contribution

Discovery of a new regulatory mechanism for nucleoside diphosphate kinase in bacteria.

## Key findings

- SixA dephosphorylates Ndk's phosphohistidine intermediate in E. coli.
- Loss of SixA regulation reduces bacterial survival in low-nutrient conditions.
- This regulatory mechanism is conserved in both bacteria and humans.

## Abstract

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.

Sinha and Goulian demonstrate that the phosphatase SixA is critical for E. coli to survive the starvation stress of long-term stationary phase. Genetic and biochemical analyses show that this survival advantage depends on SixA-mediated dephosphorylation of nucleoside diphosphate kinase, revealing a new mechanism for regulating this enzyme in bacteria.