Cyclic Dimeric Guanosine Monophosphate: Activation and Inhibition of Innate Immune Response

Abstract

Cyclic dimeric guanosine monophosphate (c-di-GMP) is a universally conserved second messenger that contributes to the pathogenicity of numerous bacterial species. In recent years, growing evidence has shown that bacterial extracellular c-di-GMP can interact with the innate immune system and regulate host immune responses. This review summarizes our current understanding on the dual roles of bacterial c-di-GMP in pathogen-host interaction: activation of the antibacterial innate immune response through the cytosolic surveillance pathway and inhibition of innate immune defense for iron restriction.

Keywords: Cyclic dimeric guanosine monophosphate; Cytosolic surveillance pathway; DDX41; Innate immune defense; Lipocalin-2; STING; Siderocalin.

Fig. 1

Activation of innate immune response by c-di-GMP. c-di-GMP can be synthesized from two GTP molecules by bacterial diguanylate cyclase. Intracellular c-di-GMP can be secreted to the bacterial extracellular space through some yet unknown pathways. c-di-GMP can further target cytosolic DDX41 and STING and regulate STING-TBK1-IRF3 immune response pathways. STING is an adaptor protein that can be activated by cyclic GMP-AMP synthesized by cytosolic cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS), which senses pathogen-derived cytosolic DNA. The transcription factor IRF3 can be translocated into the nucleus upon its phosphorylation by TBK1, leading to the activation of type I IFN gene transcription.

Fig. 2

c-di-GMP targets LCN2 and inhibits its antibacterial activity. Iron-free siderophores are secreted into the extracellular space by bacteria. Then, they chelate extracellular Fe³⁺ and form a complex. The iron-carrying siderophores are then transported into the intracellular space. Chelated Fe³⁺ is released into the cytoplasm from the siderophores. The iron-free siderophores begin their next cycle (blue arrows). The innate immune protein LCN2 blocks iron transport by capturing bacterial secreted siderophores (red arrows). Bacteria secrete c-di-GMP, which binds to LCN2 and blocks its arrest of siderophores (green arrows). The synergistic action of c-di-GMP and LCN2 facilitates bacterial Fe³⁺ acquisition from the host.