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Cited by 854interferon and immune responsesImmune Response and InflammationAutophagy in Disease and Therapy

Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response

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Saitoh, Tatsuya, Fujita, Naonobu, Hayashi, Takuya, Takahara, Keigo, Satoh, Takashi, Lee, Hanna, Matsunaga, Kohichi, Kageyama, Shun +8 more·2009·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0911267106PMC PMC2791563
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Abstract

Microbial nucleic acids are critical for the induction of innate immune responses, a host defense mechanism against infection by microbes. Recent studies have indicated that double-stranded DNA (dsDNA) induces potent innate immune responses via the induction of type I IFN (IFN) and IFN-inducible genes. However, the regulatory mechanisms underlying dsDNA-triggered signaling are not fully understood. Here we show that the translocation and assembly of the essential signal transducers, stimulator of IFN genes (STING) and TANK-binding kinase 1 (TBK1), are required for dsDNA-triggered innate immune responses. After sensing dsDNA, STING moves from the endoplasmic reticulum (ER) to the Golgi apparatus and finally reaches the cytoplasmic punctate structures to assemble with TBK1. The addition of an ER-retention signal to the C terminus of STING dampens its ability to induce antiviral responses. We also show that STING co-localizes with the autophagy proteins, microtubule-associated protein 1 light chain 3 (LC3) and autophagy-related gene 9a (Atg9a), after dsDNA stimulation. The loss of Atg9a, but not that of another autophagy-related gene (Atg7), greatly enhances the assembly of STING and TBK1 by dsDNA, leading to aberrant activation of the innate immune response. Hence Atg9a functions as a regulator of innate immunity following dsDNA stimulation as well as an essential autophagy protein. These results demonstrate that dynamic membrane traffic mediates the sequential translocation and assembly of STING, both of which are essential processes required for maximal activation of the innate immune response triggered by dsDNA.

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  • ATG9A KO mice die at a very early developmental stage.

    “ATG9A KO mice die at a very early developmental stage [53, 54].”

    From miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A (2026) · cites this paper as [54]

    The Results state that all Atg9a-knockout mice died within one day of delivery, not at an early developmental stage. The paper describes neonatal death after birth. (LLM, conf=0.88)

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • Autophagy is inhibited in ATG9A KO animals, as suggested by accumulation of p62/SQSTM1, NBR1, and ubiquitin.

    “The observed accumulation of p62/SQSTM1, NBR1, and ubiquitin suggests that autophagy is inhibited in ATG9A KO animals [53, 54].”

    From miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A (2026) · cites this paper as [54]

    The Results (page not provided) report massive p62 accumulation, reduced protein degradation, and impaired autophagosome formation in Atg9a-knockout mouse embryonic fibroblasts. They do not report NBR1 or ubiquitin accumulation, or show that these markers accumulate in knockout animals. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Authors
Saitoh, T., Fujita, N., Hayashi, T., Takahara, K., Satoh, T., Lee, H., Matsunaga, K., Kageyama, S., Omori, H., Noda, T., Yamamoto, N., Kawai, T., Ishii, K., Takeuchi, O., Yoshimori, T., & Akira, S.
Affiliations
  • Immunology Frontier Research Center, The University of Osaka (JP)
  • Department of Cellular Regulation, and
  • The University of Osaka (JP)
  • National Institute of Infectious Diseases (JP)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2009-12-08
Volume
106
Issue
49
Pages
20842-20846
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0911267106
PMC
PMC2791563
OpenAlex
W1986303112
Cited by
854
References
1
Citations by year
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FWCI
15.36
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (AI070167)
  • National Institute of Allergy and Infectious Diseases (P01AI070167, AI 070167)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
ATG9A, STING, TBK1, double-stranded DNA sensing, innate immune response, type I interferon, autophagy, membrane trafficking, Golgi apparatus, ER retention signal, LC3, antiviral signaling
MeSH terms
Autophagy-Related Proteins, STING Protein, Animals, Autophagy, Cell Membrane, DNA, Embryo, Mammalian, Endoplasmic Reticulum, Fibroblasts, Immunity, Innate, Membrane Proteins, Protein Serine-Threonine Kinases, Protein Transport, Vesicular Transport Proteins, Mice

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