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TitleThe mutational landscape of STING-induced immunity.
Journal, issue, pagesNature, Year 2026
Publish dateOct 7, 2025
AuthorsBing Zhang / Pengbiao Xu / Yu Meng / Laure Gallay / François Lestelle / Hélène Morel / Marie-Louise Frémond / Bruno E Correia / Andrea Ablasser /
PubMed AbstractStimulator of interferon genes (STING) is an evolutionary conserved immune signalling protein with key roles in host defence, cancer, senescence and inflammation. Downstream of STING, type I ...Stimulator of interferon genes (STING) is an evolutionary conserved immune signalling protein with key roles in host defence, cancer, senescence and inflammation. Downstream of STING, type I interferon, inflammatory cytokine signalling and non-canonical autophagy are governed by a multilayered mechanism integrating ligand-induced structural transitions, protein-protein interactions and coordinated intracellular trafficking. Despite its central role in immunity and relevance as therapeutic target, the sequence elements that govern STING (in)activation in cells remain incompletely understood. Here we developed a massively parallel assay to systematically chart the sequence-function landscape of STING. Profiling thousands of single amino-acid variants, we identified structural and functional determinants that shape the immunostimulatory capacity of STING and its ability to translate ligand recognition into distinct signalling outputs. Cryogenic-electron microscopy structures of select STING hyperactive variants revealed new regulatory principles dictating conformational transition from inactive to signalling-competent states of STING. Mutational effects are widespread across the functional landscape and can sensitize STING towards the natural ligand 2'3'-cGAMP or decouple interferon induction from non-canonical autophagy, demonstrating a diversity of possible responses that can be accessed through single point substitutions. Finally, our data showed the clinical and evolutionary relevance of naturally occurring STING protein variants. Collectively, these findings define molecular principles that tune STING activity and chart the landscape of its functional potential across immune contexts.
External linksNature / PubMed:42343134
MethodsEM (single particle)
Resolution2.86 - 3.38 Å
Structure data

55320

9swm

EMDB-55320, PDB-9swm:
Stimulator of interferon genes protein
Method: EM (single particle) / Resolution: 3.38 Å

55324

9swq

EMDB-55324, PDB-9swq:
Stimulator of interferon genes protein mutant - I165H
Method: EM (single particle) / Resolution: 3.31 Å

55325

9swr

EMDB-55325, PDB-9swr:
Stimulator of interferon genes protein mutant - W119K M120K
Method: EM (single particle) / Resolution: 2.86 Å

55326

9sws

EMDB-55326, PDB-9sws:
Stimulator of interferon genes protein mutant - D319K D320K
Method: EM (single particle) / Resolution: 3.04 Å

Source
  • homo sapiens (human)
KeywordsIMMUNE SYSTEM / STING / Innate Immunity

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