Acetylation of Response Regulator Proteins, TcrX and MtrA in M. tuberculosis Tunes their Phosphotransfer Ability and Modulates Two-Component Signaling Crosstalk

J Mol Biol. 2019 Feb 15;431(4):777-793. doi: 10.1016/j.jmb.2019.01.004. Epub 2019 Jan 9.


Two-component signal transduction (TCS) cascades involve stimulus-dependent activation and phosphorylation of a sensor kinase (SK), which then transfers the phosphoryl moiety to the response regulator (RR) protein. The fidelity of this phosphotransfer reaction from the SK to the RR provides specificity to TCS signaling. In the present study, we show that for TcrX, a transcriptionally autoregulated RR of Mycobacterium tuberculosis, acetylation enhances its net phosphorylation from cognate SK TcrY and lowers it from a non-cognate SK MtrB. Similar acetylation mediated increase in phosphorylation was also observed for another RR MtrA from cognate SK MtrB. Thus, we establish a novel TCS signaling design wherein acetylation of RRs results in enhanced cognate phosphorylation and suppresses non-cognate phosphorylation. Using wild-type or acetylation-deficient TcrX proteins in M. tuberculosis H37Ra, we demonstrate that non-acetylated TcrX acts as a "phosphate sink" for MtrB and suppressing signal propagation from MtrB to MtrA in vivo, linking metabolism to TCS signaling. Overall, we report that acetylation of RRs shields TCSs from crosstalk, modulates the phosphatase activities and alters the DNA-binding activities of RRs, all of which are non-intuitive behavior of TCS systems.

Keywords: Two component signaling; acetylation; crosstalk; response regulator; sensor kinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Bacterial Proteins / genetics*
  • Homeostasis / genetics
  • Mycobacterium tuberculosis / genetics*
  • Phosphorylation / genetics*
  • Phosphotransferases / genetics*
  • Signal Transduction / genetics*
  • Transcription, Genetic / genetics


  • Bacterial Proteins
  • Phosphotransferases