ArticleImmunity2023
SMPDL3A is a cGAMP-degrading enzyme induced by LXR-mediated lipid metabolism to restrict cGAS-STING DNA sensing.
Article in Immunity, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers, 1 of them a synthesis that pooled it.
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Who cites it
53 citing papers in PubMed, 1 synthesis or guideline pooled it, 101 citations in OpenAlex.
- Host Transcriptional Meta-signatures Reveal Diagnostic Biomarkers for Plasmodium falciparum Malaria.The Journal of infectious diseases · 2024Pooled it
- SLC4A9 deficiency is involved in Sjögren's syndrome and enamel defects through RPS27-triggered ribosomal stress.Experimental & molecular medicine · 2026Article
- The cGAS-STING/MITA pathway in innate antiviral immunity and beyond.Cell insight · 2026Review
- STING agonist profiling by nucleotide library defines structural determinants of cyclic dinucleotide recognition.iScience · 2026Article
- STING: An Attractive Target for Autoimmune and Inflammatory Diseases.Medicinal research reviews · 2026Review
- The cGAS/STING pathway in cancer: translating innate DNA sensing into therapeutic potential.The Journal of clinical investigation · 2026Review
- Attenuating AAV-triggered innate immunity in the adult mouse nervous systemActa pharmaceutica Sinica. B · 2026Article
- From energy metabolic homeostasis to immune remodeling: the role and therapeutic potential of STING signaling in the tumor microenvironment.Cell communication and signaling : CCS · 2026Review
- Polyamine sequestration of 2'3'-cGAMP constrains intercellular transmission and STING engagement to subvert antitumor immunity.The Journal of clinical investigation · 2026Article
- Structural genomics sheds light on protein functions and remote homologs across the insect tree of life.Cell research · 2026Article
- Extracellular cGAMP in health and disease.Molecular biomedicine · 2026Review
- DNA-PK interacts with cyclic dinucleotides and inhibits type I interferon responses.The Journal of experimental medicine · 2026Article
- DefensePredictor: A machine learning model to discover prokaryotic immune systems.Science (New York, N.Y.) · 2026Article
- The cGAS-STING pathway in cancer: friend or foe.Cell death & disease · 2026Review
- Low-dose radiotherapy remodels the tumor immune microenvironment via the cGAS-STING pathway: mechanisms, challenges, and combination therapy strategies.Molecular cancer · 2026Review
- Opportunities and challenges of targeting cGAS-STING in cancer.Nature reviews. Cancer · 2026Review
- STING controls glycolysis and histone lactylation to drive macrophage metabolic reprogramming in postoperative ileus.Communications biology · 2026Article
- Antimycin A inhibits alpha-herpesvirus replication by disrupting the formation of pyrimidinosomes.Journal of advanced research · 2026Article
- Proteome profiling reveals early diagnostic biomarker candidates for colorectal cancer.BMC cancer · 2026Article
- Lifelong cGAS deficiency leads to altered lipid storage and cholesterol homeostasis.Biological research · 2026Article
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Lipid metabolism has been associated with the cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) stimulator of interferon genes (STING) DNA-sensing pathway, but our understanding of how these signals are integrated into a cohesive immunometabolic program is lacking. Here, we have identified liver X receptor (LXR) agonists as potent inhibitors of STING signaling. We show that stimulation of lipid metabolism by LXR agonists specifically suppressed cyclic GMP-AMP (cGAMP)-STING signaling. Moreover, we developed cyclic dinucleotide-conjugated beads to biochemically isolate host effectors for cGAMP inhibition, and we found that LXR ligands stimulated the expression of sphingomyelin phosphodiesterase acid-like 3A (SMPDL3A), which is a 2'3'-cGAMP-degrading enzyme. Results of crystal structures suggest that cGAMP analog induces dimerization of SMPDL3A, and the dimerization is critical for cGAMP degradation. Additionally, we have provided evidence that SMPDL3A cleaves cGAMP to restrict STING signaling in cell culture and mouse models. Our results reveal SMPDL3A as a cGAMP-specific nuclease and demonstrate a mechanism for how LXR-associated lipid metabolism modulates STING-mediated innate immunity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.