Crystal structures of porcine STINGCBD–CDN complexes reveal the mechanism of ligand recognition and discrimination of STING proteins

Xu, Cong; Yuan, Zenglin; Du, Yijun; Wu, Bo; Lu, Defen; Wu, Xiangju; Zhang, Youjia; Li, Feng; Wei, Bin; Li, Jun; Wu, Jiaqiang; Xu, Sujuan; Wang, Jinbao; Qi, Jing; Shang, Guijun; Gu, Lichuan

doi:10.1074/jbc.ra119.007367

Cited by 25 publications

(16 citation statements)

References 36 publications

(36 reference statements)

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“…To guide alignment and phylogenetic analysis of all STING family receptors, the bacterial Fs STING, Cg STING, and oyster STING structures were superposed with human STING and representatives from all previously published metazoan STING structures 6 – 9 , 12 , 19 , 23 , 40 – 46 using the secondary-structure matching algorithm in Coot 39 , 47 . A sequence alignment was extracted from the superposed structures according to C-alpha position, and extended to include a list of all known STING protein sequences using PROMALS3D 48 .…”

Section: Methodsmentioning

confidence: 99%

STING cyclic dinucleotide sensing originated in bacteria

Morehouse

Govande

Millman

et al. 2020

Nature

265

321

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Stimulator of interferon genes (STING) is a receptor in human cells that senses foreign cyclic dinucleotides released during bacterial infection and endogenous cyclic GMP–AMP signaling during viral infection and antitumor immunity 1 – 5 . STING shares no structural homology with other known signaling proteins 6 – 9 , limiting functional analysis and preventing explanation for the origin of cyclic dinucleotide signaling in mammalian innate immunity. Here we discover functional STING homologues encoded within prokaryotic defense islands and reveal a conserved mechanism of signal activation. Crystal structures of bacterial STING define a minimal homodimeric scaffold that selectively responds to c-di-GMP synthesized by a neighboring cGAS/DncV-like nucleotidyltransferase (CD-NTase) enzyme. Bacterial STING domains couple cyclic dinucleotide recognition with protein filament formation to drive TIR effector domain oligomerization and rapid NAD + cleavage. We reconstruct the evolutionary events following acquisition of STING into metazoan innate immunity and determine the structure of a full-length TIR-STING fusion from the Pacific oyster C. gigas . Comparative structural analysis demonstrates how metazoan-specific additions to the core STING scaffold enabled a switch from direct effector function to regulation of antiviral transcription. Together, our results explain the mechanism of STING-dependent signaling and reveal conservation of a functional cGAS-STING pathway in prokaryotic bacteriophage defense.

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Section: Methodsmentioning

confidence: 99%

STING cyclic dinucleotide sensing originated in bacteria

Morehouse

Govande

Millman

et al. 2020

Nature

265

321

View full text Add to dashboard Cite

show abstract

“…Upon DNA binding in the cytoplasm, cGAS dimerizes and further oligomerizes to induce optimal cGAMP production ( Gao et al., 2013 ; Zhang et al., 2014 ). Thereafter, cGAMP binds to STING in its ligand-binding domain and induces inward rotations leading to dimerization and later oligomerization of STING ( Cong et al., 2019 ; Ergun et al., 2019 ; Shang et al., 2012 ). In addition, upon binding of cGAMP, STING exits the endoplasmic reticulum to the Golgi apparatus.…”

Section: Introductionmentioning

confidence: 99%

Activation of cGAS/STING pathway upon paramyxovirus infection

et al. 2021

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Summary During inflammatory diseases, cancer, and infection, the cGAS/STING pathway is known to recognize foreign or self-DNA in the cytosol and activate an innate immune response. Here, we report that negative-strand RNA paramyxoviruses, Nipah virus (NiV), and measles virus (MeV), can also trigger the cGAS/STING axis. Although mice deficient for MyD88, TRIF, and MAVS still moderately control NiV infection when compared with wild-type mice, additional STING deficiency resulted in 100% lethality, suggesting synergistic roles of these pathways in host protection. Moreover, deletion of cGAS or STING resulted in decreased type I interferon production with enhanced paramyxoviral infection in both human and murine cells. Finally, the phosphorylation and ubiquitination of STING, observed during viral infections, confirmed the activation of cGAS/STING pathway by NiV and MeV. Our data suggest that cGAS/STING activation is critical in controlling paramyxovirus infection and possibly represents attractive targets to develop countermeasures against severe disease induced by these pathogens.

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“…[ [137][138][139][140][141][142] Sus scrofa (6A04) [143] N. vectensis (5CFL, 5CFP) [144] GEMM Riboswitches interacts with c-di-GMP by an uncharacterized motif with high affinity, at the picomolar range, compared to c-di-GMP protein receptors, with nanomolar to micromolar affinities. In the case of c-di-GMP I Riboswitch (PDB 3IRW) the nucleotides involved in ligand binding are: G14, C15, A16, C17, A18, G19, G21, C46, A47, A48, A49, G50.…”

Section: Cyclic Dinucleotide Receptorsmentioning

confidence: 99%

The World of Cyclic Dinucleotides in Bacterial Behavior

et al. 2020

Molecules

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The regulation of multiple bacterial phenotypes was found to depend on different cyclic dinucleotides (CDNs) that constitute intracellular signaling second messenger systems. Most notably, c-di-GMP, along with proteins related to its synthesis, sensing, and degradation, was identified as playing a central role in the switching from biofilm to planktonic modes of growth. Recently, this research topic has been under expansion, with the discoveries of new CDNs, novel classes of CDN receptors, and the numerous functions regulated by these molecules. In this review, we comprehensively describe the three main bacterial enzymes involved in the synthesis of c-di-GMP, c-di-AMP, and cGAMP focusing on description of their three-dimensional structures and their structural similarities with other protein families, as well as the essential residues for catalysis. The diversity of CDN receptors is described in detail along with the residues important for the interaction with the ligand. Interestingly, genomic data strongly suggest that there is a tendency for bacterial cells to use both c-di-AMP and c-di-GMP signaling networks simultaneously, raising the question of whether there is crosstalk between different signaling systems. In summary, the large amount of sequence and structural data available allows a broad view of the complexity and the importance of these CDNs in the regulation of different bacterial behaviors. Nevertheless, how cells coordinate the different CDN signaling networks to ensure adaptation to changing environmental conditions is still open for much further exploration.

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Crystal structures of porcine STINGCBD–CDN complexes reveal the mechanism of ligand recognition and discrimination of STING proteins

Cited by 25 publications

References 36 publications

STING cyclic dinucleotide sensing originated in bacteria

STING cyclic dinucleotide sensing originated in bacteria

Activation of cGAS/STING pathway upon paramyxovirus infection

The World of Cyclic Dinucleotides in Bacterial Behavior

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