Publications

Novel binding proteins of Cyclic AMP coordinate growth and competence of Haemophilus influenzae 

JBC 2023

Haemophilus influenzae is an important human pathogen, causing respiratory tract infection including pneumonia. Extensive drug resistance is observed in H. influenzae species, which is attributed to their well-described natural competence system. Natural competence is a physiological state that some bacteria, under certain conditions, become active to take up external DNA and integrate it into the chromosome. External DNA may contain an antibiotic resistance gene and thereby confer antibiotic resistance to H. influenzae. Therefore, it is important to understand how natural competence of H. influenzae is regulated by external cues. 

Previously, it was found that the secondary messenger cyclic AMP (cAMP) activates while purine nucleotides inhibit the competence development of H. influenzae Rd KW20. However, the interplay between cAMP and nucleotides remains incompletely understood. Here we show that cAMP competitively inhibits three periplasmic phosphatases of KW20 and thereby inhibits the utilization of nutritional nucleotides and the essential growth factor NAD. Via this mechanism, cAMP activates the competence development of KW20 only after external nucleotides are sufficiently depleted, thereby coupling growth arrest with competence development. Similar mechanisms are anticipated to function in bacteria closely related to Haemophilus influenzaee, and Vibrio cholerae, another important human pathogen.

ppGpp stimulates PpnN to balance competitive growth and persistence

Mol Cell 2019

During stringent response, ppGpp feedback inhibits numerous enzymes involved in the purine nucleotide biosynthesis, including both the de novo and salvage pathways. Recently, we surprisingly found a nucleosidase PpnN, cleaving NMP to nucleobases, as a target protein of ppGpp. By integrative use of biochemistry, crystallography, metabolomics and physiology, we discovered that ppGpp allosterically stimulate the catalytic activity of PpnN, which regulates E. coli in achieving balanced adaptation to constantly changing environments with fluctuating levels of nutrient and stress. Such a mechanism is highly conserved in Proteobacteria including many important pathogens.

Novel ppGpp target proteins

mBio 2018

The universal stringent alarmone ppGpp plays pivotal roles in bacterial tolerance to stresses including antibiotic insults. However, mechanistic understandings of ppGpp functions have been hampered by the incomplete knowledge of its target proteins. Using a systems biology tool called DRaCALA, we recently identified many novel ppGpp binding proteins in E. coli, a milestone since the first discovery of ppGpp over 50 years ago. Current work focuses on in depth understanding of ppGpp and its target proteins in bacterial stress response and persistence.  

List of Publications