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Tonic prime-boost of STING signalling mediates Niemann–Pick disease type C

Author

Listed:
  • Ting-Ting Chu

    (University of Texas Southwestern Medical Center)

  • Xintao Tu

    (University of Texas Southwestern Medical Center)

  • Kun Yang

    (University of Texas Southwestern Medical Center)

  • Jianjun Wu

    (University of Texas Southwestern Medical Center)

  • Joyce J. Repa

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

  • Nan Yan

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

Abstract

The classic mode of STING activation is through binding the cyclic dinucleotide 2′3′-cyclic GMP–AMP (cGAMP), produced by the DNA sensor cyclic GMP–AMP synthase (cGAS), which is important for the innate immune response to microbial infection and autoimmune disease. Modes of STING activation that are independent of cGAS are much less well understood. Here, through a spatiotemporally resolved proximity labelling screen followed by quantitative proteomics, we identify the lysosomal membrane protein Niemann–Pick type C1 (NPC1) as a cofactor in the trafficking of STING. NPC1 interacts with STING and recruits it to the lysosome for degradation in both human and mouse cells. Notably, we find that knockout of Npc1 ‘primes’ STING signalling by physically linking or ‘tethering’ STING to SREBP2 trafficking. Loss of NPC1 protein also ‘boosts’ STING signalling by blocking lysosomal degradation. Both priming and boosting of STING signalling are required for severe neurological disease in the Npc1−/− mouse. Genetic deletion of Sting1 (the gene that encodes STING) or Irf3, but not that of Cgas, significantly reduced the activation of microglia and relieved the loss of Purkinje neurons in the cerebellum of Npc1−/− mice, leading to improved motor function. Our study identifies a cGAS- and cGAMP-independent mode of STING activation that affects neuropathology and provides a therapeutic target for the treatment of Niemann–Pick disease type C.

Suggested Citation

  • Ting-Ting Chu & Xintao Tu & Kun Yang & Jianjun Wu & Joyce J. Repa & Nan Yan, 2021. "Tonic prime-boost of STING signalling mediates Niemann–Pick disease type C," Nature, Nature, vol. 596(7873), pages 570-575, August.
  • Handle: RePEc:nat:nature:v:596:y:2021:i:7873:d:10.1038_s41586-021-03762-2
    DOI: 10.1038/s41586-021-03762-2
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    Citations

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    Cited by:

    1. Xintao Tu & Ting-Ting Chu & Devon Jeltema & Kennady Abbott & Kun Yang & Cong Xing & Jie Han & Nicole Dobbs & Nan Yan, 2022. "Interruption of post-Golgi STING trafficking activates tonic interferon signaling," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Matteo Gentili & Bingxu Liu & Malvina Papanastasiou & Deborah Dele-Oni & Marc A. Schwartz & Rebecca J. Carlson & Aziz M. Al’Khafaji & Karsten Krug & Adam Brown & John G. Doench & Steven A. Carr & Nir , 2023. "ESCRT-dependent STING degradation inhibits steady-state and cGAMP-induced signalling," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    3. Zhibin Lin & Peijun Yang & Yufeng Hu & Hao Xu & Juanli Duan & Fei He & Kefeng Dou & Lin Wang, 2023. "RING finger protein 13 protects against nonalcoholic steatohepatitis by targeting STING-relayed signaling pathways," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    4. Bao-cun Zhang & Marlene F. Laursen & Lili Hu & Hossein Hazrati & Ryo Narita & Lea S. Jensen & Aida S. Hansen & Jinrong Huang & Yan Zhang & Xiangning Ding & Maimaitili Muyesier & Emil Nilsson & Agniesz, 2024. "Cholesterol-binding motifs in STING that control endoplasmic reticulum retention mediate anti-tumoral activity of cholesterol-lowering compounds," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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