Cell signaling is universally controlled by reversible protein phosphorylation. In prokaryotes, phosphorylation on histidine and aspartate was long considered the main signaling mechanism, but phosphorylation on serine (Ser), threonine (Thr), and tyrosine (Tyr) is now emerging as equally important. In Mycobacterium tuberculosis (Mtb), signaling through Ser/Thr phosphorylation is essential. Phosphorylation on Tyr, however, has not yet been described and is thought to be absent. We now for the first time show protein tyrosine phosphorylation in Mtb. We unambiguously detected 25 phosphorylation sites on 16 proteins in a single growth condition. We show tyrosine phosphorylation activity of two Mtb Ser/Thr kinases (STPKs), suggesting that some STPKs are dual specificity kinases. Further, we show that Tyr phosphorylation controls the overall activity of the essential STPK PknB. Because PknB is essential for Mtb growth, other STPKs broadly regulate Mtb adaptations, and tyrosine phosphorylation determines virulence in other bacteria, these findings have wide implications for Mtb pathogenesis. Here, we will identify the kinases and phosphatases that mediate Mtb protein phosphorylation on Tyr.

Public Health Relevance

Pathogens respond to their environment by transmitting extracellular signals into appropriate responses by phosphosignaling. While phosphorylation on serine and threonine residues has been previously shown to control Mycobacterium tuberculosis (Mtb) pathogenesis, phosphorylation on tyrosine residues is currently thought to be absent. Here, we for the first time show this signaling mechanism in Mtb and propose to identify the relevant enzymes that mediate tyrosine phosphorylation.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI111330-01
Application #
8684722
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lacourciere, Karen A
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Seattle Biomedical Research Institute
Department
Type
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98109