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Innate immune signalling

Lipid metabolism extinguishes cGAS–STING-induced inflammation

Nature Reviews Immunology volume 23, page 785 (2023)Cite this article

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The DNA-sensing cGAS–cGAMP–STING pathway, which drives the production of type I interferon (IFN) and other proinflammatory cytokines, must be tightly regulated to avoid chronic or autoinflammatory responses. Many studies have suggested cross-regulation between lipid metabolism and innate immune pathways, in particular the anti-inflammatory effects of liver X receptor (LXR) signalling, but the mechanisms have been unclear. Hou et al. report that LXR agonists inhibit STING signalling by promoting degradation of the second messenger 2′3′-cyclic GMP–AMP (cGAMP).

Biochemical studies of SMPDL3A activity suggested that it linearizes and then hydrolyses 2′3′-cGAMP, and the X-ray crystal structure of SMPDL3A bound to a cGAMP analogue suggested that dimerization of SMPDL3A is required for its enzymatic activity. Mutant forms of SMPDL3A lacking crucial residues of the dimer-binding interface were not able to hydrolyse cGAMP.

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  1. Nature Reviews Immunology http://www.nature.com/nri/

    Kirsty Minton

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  1. Kirsty Minton
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Correspondence to Kirsty Minton.

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Minton, K. Lipid metabolism extinguishes cGAS–STING-induced inflammation. Nat Rev Immunol 23, 785 (2023). https://doi.org/10.1038/s41577-023-00962-x

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