TY - JOUR
T1 - Tonic prime-boost of STING signalling mediates Niemann–Pick disease type C
AU - Chu, Ting Ting
AU - Tu, Xintao
AU - Yang, Kun
AU - Wu, Jianjun
AU - Repa, Joyce J.
AU - Yan, Nan
N1 - Funding Information:
Acknowledgements We thank G. Barber for Sting1−/−mice, K. Fitzgerald and T. Taniguchi for Irf3−/− mice, Z. Chen for Cgas−/− and Mavs−/− mice and J. Dietschy for Npc2+/− mice; D. Ramirez, W. Li and A. Nawaby at the University of Texas Southwestern (UTSW) Whole Brain Microscopy Core Facility (RRID:SCR_017949) for assistance with tissue sectioning, histological staining, immunostaining and slide scanning; A. Lemoff at the UTSW Proteomics Core Facility for assistance with TMT-MS experiments; R. Hammer and M. Nguyen at the UTSW Transgenic Technology Center for creating Npc1−/−Sting1−/− mice; K. Phelps and A. Bugde at the UTSW Live Cell Imaging Facility, a Shared Resource of the Harold C. Simmons Cancer Center, supported in part by NCI Cancer Center Support Grant 1P30 CA142543-01 and National Institutes of Health (NIH) Shared Instrumentation Award 1S10 OD021684-01; I. Raman at the UTSW Medical Center Genomics and Microarray Core; and P. Tsai and members of the Yan laboratory for discussions. This work was supported by the NIH (AI151708 and NS122825 to N.Y.), the Cancer Prevention and Research Institute of Texas (CPRIT; RP180288 to N.Y.), the Burroughs Wellcome Fund (N.Y.) and the Ara Parseghian Medical Research Foundation (J.J.R.).
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/8/26
Y1 - 2021/8/26
N2 - 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.
AB - 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.
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U2 - 10.1038/s41586-021-03762-2
DO - 10.1038/s41586-021-03762-2
M3 - Article
C2 - 34290407
AN - SCOPUS:85110935001
VL - 596
SP - 570
EP - 575
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7873
ER -