Tonic prime-boost of STING signalling mediates Niemann-Pick disease type C.
Animals
Cell Line
Cerebellum
/ pathology
Endoplasmic Reticulum
/ metabolism
Golgi Apparatus
/ metabolism
Humans
Interferon Regulatory Factor-3
/ metabolism
Interferon Type I
/ immunology
Lysosomes
/ metabolism
Membrane Proteins
/ deficiency
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Microglia
/ metabolism
Models, Biological
Motor Skills
Neuroinflammatory Diseases
Niemann-Pick C1 Protein
/ deficiency
Niemann-Pick Disease, Type C
/ metabolism
Nucleotides, Cyclic
/ metabolism
Nucleotidyltransferases
/ metabolism
Protein Serine-Threonine Kinases
/ metabolism
Protein Transport
Proteolysis
Purkinje Cells
/ metabolism
Signal Transduction
Sterol Regulatory Element Binding Protein 2
/ metabolism
Journal
Nature
ISSN: 1476-4687
Titre abrégé: Nature
Pays: England
ID NLM: 0410462
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
received:
12
10
2020
accepted:
23
06
2021
pubmed:
23
7
2021
medline:
12
2
2022
entrez:
22
7
2021
Statut:
ppublish
Résumé
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
Identifiants
pubmed: 34290407
doi: 10.1038/s41586-021-03762-2
pii: 10.1038/s41586-021-03762-2
pmc: PMC8859990
mid: NIHMS1778344
doi:
Substances chimiques
Interferon Regulatory Factor-3
0
Interferon Type I
0
Irf3 protein, mouse
0
Membrane Proteins
0
NPC1 protein, human
0
Niemann-Pick C1 Protein
0
Npc1 protein, mouse
0
Nucleotides, Cyclic
0
STING1 protein, human
0
Sterol Regulatory Element Binding Protein 2
0
Sting1 protein, mouse
0
cyclic guanosine monophosphate-adenosine monophosphate
0
Tbk1 protein, mouse
EC 2.7.1.-
Protein Serine-Threonine Kinases
EC 2.7.11.1
TBK1 protein, human
EC 2.7.11.1
Nucleotidyltransferases
EC 2.7.7.-
cGAS protein, mouse
EC 2.7.7.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
570-575Subventions
Organisme : NIA NIH HHS
ID : P30 AG021684
Pays : United States
Organisme : NIH HHS
ID : S10 OD021684
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI151708
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA142543
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS122825
Pays : United States
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
Références
Chin, A. C. Neuroinflammation and the cGAS–STING pathway. J. Neurophysiol. 121, 1087–1091 (2019).
doi: 10.1152/jn.00848.2018
Yan, N. Immune diseases associated with TREX1 and STING dysfunction. J. Interferon Cytokine Res. 37, 198–206 (2017).
doi: 10.1089/jir.2016.0086
Sliter, D. A. et al. Parkin and PINK1 mitigate STING-induced inflammation. Nature 561, 258–262 (2018).
doi: 10.1038/s41586-018-0448-9
Yang, K., Huang, R., Fujihira, H., Suzuki, T. & Yan, N. N-glycanase NGLY1 regulates mitochondrial homeostasis and inflammation through NRF1. J. Exp. Med. 215, 2600–2616 (2018).
doi: 10.1084/jem.20180783
Yu, C.-H. et al. TDP-43 triggers mitochondrial DNA release via mPTP to activate cGAS/STING in ALS. Cell 183, 636–649 (2020).
doi: 10.1016/j.cell.2020.09.020
Wu, J. et al. STING-mediated disruption of calcium homeostasis chronically activates ER stress and primes T cell death. J. Exp. Med. 216, 867–883 (2019).
doi: 10.1084/jem.20182192
Warner, J. D. et al. STING-associated vasculopathy develops independently of IRF3 in mice. J. Exp. Med. 214, 3279–3292 (2017).
doi: 10.1084/jem.20171351
Luksch, H. et al. STING-associated lung disease in mice relies on T cells but not type I interferon. J. Allergy Clin. Immunol. 144, 254–266.e8 (2019).
doi: 10.1016/j.jaci.2019.01.044
Motwani, M. et al. Hierarchy of clinical manifestations in SAVI N153S and V154M mouse models. Proc. Natl Acad. Sci. USA 116, 7941–7950 (2019).
doi: 10.1073/pnas.1818281116
Dobbs, N. et al. STING activation by translocation from the ER is associated with infection and autoinflammatory disease. Cell Host Microbe 18, 157–168 (2015).
doi: 10.1016/j.chom.2015.07.001
Barber, G. N. STING-dependent signaling. Nat. Immunol. 12, 929–930 (2011).
doi: 10.1038/ni.2118
Wu, J., Dobbs, N., Yang, K. & Yan, N. Interferon-independent activities of mammalian STING mediate antiviral response and tumor immune evasion. Immunity 53, 115–126 (2020).
doi: 10.1016/j.immuni.2020.06.009
Gonugunta, V. K. et al. Trafficking-mediated STING degradation requires sorting to acidified endolysosomes and can be targeted to enhance anti-tumor response. Cell Rep. 21, 3234–3242 (2017).
doi: 10.1016/j.celrep.2017.11.061
Pokatayev, V. et al. Homeostatic regulation of STING protein at the resting state by stabilizer TOLLIP. Nat. Immunol. 21, 158–167 (2020).
doi: 10.1038/s41590-019-0569-9
Hung, V. et al. Spatially resolved proteomic mapping in living cells with the engineered peroxidase APEX2. Nat. Protoc. 11, 456–475 (2016).
doi: 10.1038/nprot.2016.018
Gui, X. et al. Autophagy induction via STING trafficking is a primordial function of the cGAS pathway. Nature 567, 262–266 (2019).
doi: 10.1038/s41586-019-1006-9
Srikanth, S. et al. The Ca
doi: 10.1038/s41590-018-0287-8
Brown, M. S., Radhakrishnan, A. & Goldstein, J. L. Retrospective on cholesterol homeostasis: the central role of Scap. Annu. Rev. Biochem. 87, 783–807 (2018).
doi: 10.1146/annurev-biochem-062917-011852
Chen, W. et al. ER adaptor SCAP translocates and recruits IRF3 to perinuclear microsome induced by cytosolic microbial DNAs. PLoS Pathog. 12, e1005462 (2016).
doi: 10.1371/journal.ppat.1005462
Taylor, A. M., Liu, B., Mari, Y., Liu, B. & Repa, J. J. Cyclodextrin mediates rapid changes in lipid balance in Npc1
doi: 10.1194/jlr.M028241
Duncan, E. A., Brown, M. S., Goldstein, J. L. & Sakai, J. Cleavage site for sterol-regulated protease localized to a Leu–Ser bond in the lumenal loop of sterol regulatory element-binding protein-2. J. Biol. Chem. 272, 12778–12785 (1997).
doi: 10.1074/jbc.272.19.12778
Hua, X. et al. SREBP-2, a second basic-helix-loop-helix-leucine zipper protein that stimulates transcription by binding to a sterol regulatory element. Proc. Natl Acad. Sci. USA 90, 11603–11607 (1993).
doi: 10.1073/pnas.90.24.11603
Li, X. et al. Structure of human Niemann–Pick C1 protein. Proc. Natl Acad. Sci. USA 113, 8212–8217 (2016).
doi: 10.1073/pnas.1607795113
Chu, B.-B. et al. Cholesterol transport through lysosome–peroxisome membrane contacts. Cell 161, 291–306 (2015).
doi: 10.1016/j.cell.2015.02.019
Fog, C. K. & Kirkegaard, T. Animal models for Niemann–Pick type C: implications for drug discovery & development. Expert Opin. Drug Discov. 14, 499–509 (2019).
doi: 10.1080/17460441.2019.1588882
Elrick, M. J. et al. Conditional Niemann–Pick C mice demonstrate cell autonomous Purkinje cell neurodegeneration. Hum. Mol. Genet. 19, 837–847 (2010).
doi: 10.1093/hmg/ddp552
Guyenet, S. J. et al. A simple composite phenotype scoring system for evaluating mouse models of cerebellar ataxia. J. Vis. Exp. 39, e1787 (2010).
Shin, S. D. K. et al. Interferon downstream signaling is activated early in pre-symptomatic Niemann–Pick disease type C. Neurosci. Lett. 706, 43–50 (2019).
doi: 10.1016/j.neulet.2019.05.005
Parra, J. et al. Npc1 deficiency in the C57BL/6J genetic background enhances Niemann–Pick disease type C spleen pathology. Biochem. Biophys. Res. Commun. 413, 400–406 (2011).
doi: 10.1016/j.bbrc.2011.08.096
Cougnoux, A. et al. Microglia activation in Niemann–Pick disease, type C1 is amendable to therapeutic intervention. Hum. Mol. Genet. 27, 2076–2089 (2018).
doi: 10.1093/hmg/ddy112
Sleat, D. E. et al. Genetic evidence for nonredundant functional cooperativity between NPC1 and NPC2 in lipid transport. Proc. Natl Acad. Sci. USA 101, 5886–5891 (2004).
doi: 10.1073/pnas.0308456101
Dixit, S. S. et al. Loss of Niemann–Pick C1 or C2 protein results in similar biochemical changes suggesting that these proteins function in a common lysosomal pathway. PLoS ONE 6, e23677 (2011).
doi: 10.1371/journal.pone.0023677
Decout, A., Katz, J. D., Venkatraman, S. & Ablasser, A. The cGAS–STING pathway as a therapeutic target in inflammatory diseases. Nat. Rev. Immunol. https://doi.org/10.1038/s41577-021-00524-z (2021).