Abstract
The cGAS-STING pathway is a critical regulator of type I Interferon (IFN) and inflammation upon cytosolic DNA-sensing. cGAS-STING signaling termination is regulated by lysosomal-mediated degradation of STING; however, the mechanisms controlling the inhibitory targeting of STING are incompletely understood. Here, we identify the selective autophagy receptor TAX1BP1 as a negative regulator of the cGAS-STING pathway. TAX1BP1-deficient macrophages activated by cGAS or STING agonists accumulate higher-order STING aggregates, exhibit heightened STING signaling, and increased production of type I IFN and proinflammatory cytokines. Mechanistically, TAX1BP1 promotes STING degradation through microautophagy by facilitating the interaction of STING with the ESCRT-0 protein HGS. Furthermore, STING activation is associated with the swelling and fragmentation of the Golgi apparatus, and TAX1BP1 and p62/SQSTM1 are essential for the autophagic degradation of fragmented Golgi (Golgiphagy). Our findings suggest that STING activation at the Golgi is coupled to its downregulation by Golgiphagy to restrict innate immune responses.
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Acknowledgements
We thank Dr. John Wills (Penn State College of Medicine) and Lynn Enquist (Princeton University) for HSV-1 YFP, Dr. Richard Youle (National Institutes of Health) for TAX1BP1-KO HeLa cells, Dr. Nan Yan (UT Southwestern) for STING-eGFP plasmid and Dr. Adolfo García-Sastre (Icahn School of Medicine at Mount Sinai) for Mx-1 GFP mice. We thank John Tawil for the critical reading of the manuscript. We also acknowledge Dr. Loic Dragin for initial contributions to this project. We thank Dr. Han Chen for assistance with TEM studies. The experiments in this manuscript used the Penn State College of Medicine Advanced Light Microscopy Core, TEM Core and the Flow Cytometry Core. The Advanced Light Microscopy Core (RRID: SCR_022526), the TEM Core (RRID:SCR_021200) and Flow Cytometry Core (RRID:SCR_021134), services and instruments used in this project were funded, in part, by the Pennsylvania State University College of Medicine via the Office of the Vice Dean of Research and Graduate Students and the Pennsylvania Department of Health using Tobacco Settlement Funds (CURE). The content is solely the responsibility of the authors and does not necessarily represent the official views of the University or the College of Medicine. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations, or conclusions. This work was supported by NIH grant R01 AI162815 (to E.W.H.).
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S.S., S.M., C.C.N. and E.W.H. designed the experiments. S.S. and S.M. performed most of the experiments. I.E.R. and C.C.N. performed the Ectromelia infections in mice. S.S., S.M., J.W., C.C.N. and E.W.H. analyzed the data. Y.B.C. and S.M.M. performed initial experiments and Y.B.C. also performed the NanoBiT assays and generated the Golgiphagy reporter. N.S. contributed to the generation of Tax1bp1fl/fl mice. D.C. performed bioinformatics analysis. E.W.H. and S.S. wrote the manuscript. S.S., S.M., J.W., Y.B.C. and C.C.N. edited the manuscript. E.W.H. conceived and supervised the project and acquired funding for it. All authors reviewed and approved the manuscript.
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Suklabaidya, S., Mohanty, S., Reider, I.E. et al. Negative feedback regulation of STING signaling by TAX1BP1-directed Golgiphagy. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69422-z
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DOI: https://doi.org/10.1038/s41467-026-69422-z
