Tuning the Innate Immune Response to Cyclic Dinucleotides by Using Atomic Mutagenesis.
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ABSTRACT:
SUBMITTER: Li Y
PROVIDER: S-EPMC7494572 | biostudies-literature | 2020 Sep
REPOSITORIES: biostudies-literature
Publications
Tuning the Innate Immune Response to Cyclic Dinucleotides by Using Atomic Mutagenesis.
Li Yao Y Fin Andrea A Rovira Alexander R AR Su Yichi Y Dippel Andrew B AB Valderrama Jonathan Andrés JA Riestra Angelica M AM Nizet Victor V Hammond Ming C MC Tor Yitzhak Y
Chembiochem : a European journal of chemical biology 20200608 18
Cyclic dinucleotides (CDNs) trigger the innate immune response in eukaryotic cells through the stimulator of interferon genes (STING) signaling pathway. To decipher this complex cellular process, a better correlation between structure and downstream function is required. Herein, we report the design and immunostimulatory effect of a novel group of c-di-GMP analogues. By employing an "atomic mutagenesis" strategy, changing one atom at a time, a class of gradually modified CDNs was prepared. These ...[more]
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Project description:Cyclic dinucleotides (CDNs) have been previously recognized as important secondary signaling molecules in bacteria and, more recently, in mammalian cells. In the former case, they represent secondary messengers affecting numerous responses of the prokaryotic cell, whereas in the latter, they act as agonists of the innate immune response. Remarkable new discoveries have linked these two patterns of utilization of CDNs as secondary messengers and have revealed unexpected influences they likely had on shaping human genetic variation. This Review summarizes these recent insights and provides a perspective on future unanswered questions in this exciting field.
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2019-09-01 | GSE134371 | GEO
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Project description:SLC19A1 transports immunoreactive cyclic dinucleotides
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Project description: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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