title: Cyclic diguanylate monophosphate directly binds to human siderocalin and inhibits its antibacterial activity.
abstract: Cyclic diguanylate monophosphate (c-di-GMP) is a well-conserved second messenger in bacteria. During infection, the innate immune system can also sense c-di-GMP; however, whether bacterial pathogens utilize c-di-GMP as a weapon to fight against host defense for survival and possible mechanisms underlying this process remain poorly understood. Siderocalin (LCN2) is a key antibacterial component of the innate immune system and sequesters bacterial siderophores to prevent acquisition of iron. Here we show that c-di-GMP can directly target the human LCN2 protein to inhibit its antibacterial activity. We demonstrate that c-di-GMP specifically binds to LCN2. In addition, c-di-GMP can compete with bacterial ferric siderophores to bind LCN2. Furthermore, c-di-GMP can significantly reduce LCN2-mediated inhibition on the in vitro growth of Escherichia coli. Thus, LCN2 acts as a c-di-GMP receptor. Our findings provide insight into the mechanism by which bacteria utilize c-di-GMP to interfere with the innate immune system for survival.
authors.affiliation: National Key Laboratory of Agricultural Microbiology, Center for Proteomics Research, College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
authors.forename: Weihui
authors.initials: W
authors.lastname: Li
authors.affiliation: National Key Laboratory of Agricultural Microbiology, Center for Proteomics Research, College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Cui
authors.affiliation: National Key Laboratory of Agricultural Microbiology, Center for Proteomics Research, College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Hu
authors.affiliation: National Key Laboratory of Agricultural Microbiology, Center for Proteomics Research, College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
authors.forename: Ziqing
authors.initials: Z
authors.lastname: Wang
authors.affiliation: National Key Laboratory of Agricultural Microbiology, Center for Proteomics Research, College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
authors.forename: Zongqiang
authors.initials: Z
authors.lastname: Li
authors.affiliation: National Key Laboratory of Agricultural Microbiology, Center for Proteomics Research, College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.
authors.forename: Zheng-Guo
authors.initials: ZG
authors.lastname: He
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism; D016208:Databases, Factual; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D011994:Recombinant Proteins
chemical_list: D000209:Acute-Phase Proteins; D000900:Anti-Bacterial Agents; D002352:Carrier Proteins; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; C062025:bis(3',5')-cyclic diguanylic acid; D006152:Cyclic GMP