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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.
AuthorsWeihui Li, Tao Cui, Lihua Hu, Ziqing Wang, Zongqiang Li, Zheng-Guo He
JournalNature communications (Nat Commun) Vol. 6 Pg. 8330 (Sep 22 2015) ISSN: 2041-1723 [Electronic] England
PMID26390966 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Acute-Phase Proteins
  • Anti-Bacterial Agents
  • Carrier Proteins
  • LCN2 protein, human
  • Lipocalin-2
  • Lipocalins
  • Proto-Oncogene Proteins
  • Recombinant Proteins
  • bis(3',5')-cyclic diguanylic acid
  • Cyclic GMP
Topics
  • Acute-Phase Proteins (genetics, metabolism, pharmacology)
  • Anti-Bacterial Agents (metabolism)
  • Carrier Proteins (genetics, metabolism)
  • Cyclic GMP (analogs & derivatives, metabolism)
  • Databases, Factual
  • Escherichia coli (genetics, metabolism)
  • Gene Expression Regulation
  • Humans
  • Lipocalin-2
  • Lipocalins (genetics, metabolism, pharmacology)
  • Models, Chemical
  • Models, Molecular
  • Molecular Structure
  • Mycobacterium tuberculosis (drug effects, metabolism)
  • Protein Binding
  • Protein Conformation
  • Proto-Oncogene Proteins (genetics, metabolism, pharmacology)
  • Recombinant Proteins

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