Proteolysis and multimerization regulate signaling along the two-component regulatory system AdeRS
Zhenlin Ouyang,
Fang Zheng,
Li Zhu,
Jan Felix,
Di Wu,
Ke Wu,
Irina Gutsche,
Yi Wu,
Peter M. Hwang,
Junjun She,
Yurong Wen
Affiliations
Zhenlin Ouyang
Talent Highland and Center for Gut Microbiome Research of Med-X Institute, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China
Fang Zheng
The Key Laboratory of Environment and Genes Related to Disease of Ministry of Education, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China
Li Zhu
MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, China
Jan Felix
Institut de Biologie Structurale, Univ. Grenoble Alpes, CEA, CNRS, IBS, 71 avenue des Martyrs, Grenoble F-38044, France
Di Wu
MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, China
Ke Wu
MOE Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou, China
Irina Gutsche
Institut de Biologie Structurale, Univ. Grenoble Alpes, CEA, CNRS, IBS, 71 avenue des Martyrs, Grenoble F-38044, France
Yi Wu
The Key Laboratory of Environment and Genes Related to Disease of Ministry of Education, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China
Peter M. Hwang
Departments of Medicine and Biochemistry, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta T6G 2R3, Canada
Junjun She
Talent Highland and Center for Gut Microbiome Research of Med-X Institute, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China; Corresponding author
Yurong Wen
Talent Highland and Center for Gut Microbiome Research of Med-X Institute, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China; The Key Laboratory of Environment and Genes Related to Disease of Ministry of Education, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, China; Corresponding author
Summary: Bacterial two-component regulatory systems are ubiquitous environment-sensing signal transducers involved in pathogenesis and antibiotic resistance. The Acinetobacter baumannii two-component regulatory system AdeRS is made up of a sensor histidine kinase AdeS and a cognate response regulator AdeR, which together reduce repression of the multidrug-resistant efflux pump AdeABC. Herein we demonstrate that an N-terminal intrinsically disordered tail in AdeR is important for the upregulation of adeABC expression, although it greatly increases the susceptibility of AdeR to proteasome-mediated degradation. We also show that AdeS assembles into a hexameric state that is necessary for its full histidine kinase activity, which appears to occur via cis autophosphorylation. Taken together, this study demonstrates new structural mechanisms through which two-component systems can transduce environmental signals to impact gene expression and enlightens new potential antimicrobial approach by targeting two-component regulatory systems.
