NPC1-mTORC1 Signaling Couples Cholesterol Sensing to Organelle Homeostasis and Is a Targetable Pathway in Niemann-Pick Type C

Oliver B. Davis; Hijai R. Shin; Chun-Yan Lim; Emma Y. Wu; Matthew Kukurugya; Claire F. Maher; Rushika M. Perera; M. Paulina Ordonez; Roberto Zoncu

doi:10.1016/j.devcel.2020.11.016

journal article Open Access Feb 01, 2021

NPC1-mTORC1 Signaling Couples Cholesterol Sensing to Organelle Homeostasis and Is a Targetable Pathway in Niemann-Pick Type C

Oliver B. Davis Hijai R. Shin Chun-Yan Lim

Emma Y. Wu Matthew Kukurugya Claire F. Maher Rushika M. Perera M. Paulina Ordonez Roberto Zoncu

Developmental Cell Vol. 56 No. 3 pp. 260-276.e7 · Elsevier BV

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References

101

[1]

Abu-Remaileh "Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes" Science (2017) 10.1126/science.aan6298

[2]

Anandapadamanaban "Architecture of human Rag GTPase heterodimers and their complex with mTORC1" Science (2019) 10.1126/science.aax3939

[3]

Andrzejewska "Cystinosin is a component of the vacuolar H+-ATPase-ragulator-rag complex controlling mammalian target of rapamycin complex 1 signaling" J. Am. Soc. Nephrol. (2016) 10.1681/asn.2014090937

[4]

Ballabio "Lysosomal disorders: from storage to cellular damage" Biochim. Biophys. Acta (2009) 10.1016/j.bbamcr.2008.12.001

[5]

Bar-Peled "Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1" Cell (2012) 10.1016/j.cell.2012.07.032

[6]

Bartolomeo "mTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy" J. Clin. Invest. (2017) 10.1172/jci94130

[7]

Ben-Sahra "mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle" Science (2016) 10.1126/science.aad0489

[8]

Bentzinger "Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy" Cell Metab. (2008) 10.1016/j.cmet.2008.10.002

[9]

Brown "mTOR hyperactivity mediates lysosomal dysfunction in Gaucher’s disease iPSC-neuronal cells" Dis. Model Mech. (2019) 10.1242/dmm.038596

[10]

Burgett "Natural products reveal cancer cell dependence on oxysterol-binding proteins" Nat. Chem. Biol. (2011) 10.1038/nchembio.625

[11]

Calvo "MitoCarta2.0: an updated inventory of mammalian mitochondrial proteins" Nucleic Acids Res. (2016) 10.1093/nar/gkv1003

[12]

Castellano "Lysosomal cholesterol activates mTORC1 via an SLC38A9-Niemann-Pick C1 signaling complex" Science (2017) 10.1126/science.aag1417

[13]

Chiaruttini "Relaxation of loaded ESCRT-III spiral springs drives membrane deformation" Cell (2015) 10.1016/j.cell.2015.10.017

[14]

Chung "Genetic and pharmacological evidence implicates cathepsins in Niemann-Pick C cerebellar degeneration" Hum. Mol. Genet. (2016) 10.1093/hmg/ddw025

[15]

Chung "Covalent targeting of the vacuolar H+-ATPase activates autophagy via mTORC1 inhibition" Nat. Chem. Biol. (2019) 10.1038/s41589-019-0308-4

[16]

Csibi "The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4" Cell (2013) 10.1016/j.cell.2013.04.023

[17]

Cunningham "mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex" Nature (2007) 10.1038/nature06322

[18]

Danyukova "Loss of CLN7 results in depletion of soluble lysosomal proteins and impaired mTOR reactivation" Hum. Mol. Genet. (2018) 10.1093/hmg/ddy076

[19]

de Araujo "Crystal structure of the human lysosomal mTORC1 scaffold complex and its impact on signaling" Science (2017) 10.1126/science.aao1583

[20]

Dong "Endosome-ER contacts control actin nucleation and retromer function through VAP-dependent regulation of PI4P" Cell (2016) 10.1016/j.cell.2016.06.037

[21]

Düvel "Activation of a metabolic gene regulatory network downstream of mTOR complex 1" Mol. Cell (2010) 10.1016/j.molcel.2010.06.022

[22]

Ebrahimi-Fakhari "Impaired mitochondrial dynamics and mitophagy in neuronal models of tuberous sclerosis complex" Cell Rep. (2016) 10.1016/j.celrep.2016.09.054

[23]

Elrick "Impaired proteolysis underlies autophagic dysfunction in Niemann-Pick type C disease" Hum. Mol. Genet. (2012) 10.1093/hmg/dds324

[24]

Feltes "Monitoring the itinerary of lysosomal cholesterol in Niemann-Pick Type C1-deficient cells after cyclodextrin treatment" J. Lipid Res. (2020) 10.1194/jlr.ra119000571

[25]

Gao "Cholesterol-induced conformational changes in the sterol-sensing domain of the Scap protein suggest feedback mechanism to control cholesterol synthesis" J. Biol. Chem. (2017) 10.1074/jbc.m117.783894

[26]

Gong "Structural insights into the Niemann-Pick C1 (NPC1)-mediated cholesterol transfer and Ebola infection" Cell (2016) 10.1016/j.cell.2016.05.022

[27]

Hämälistö "Spatially and temporally defined lysosomal leakage facilitates mitotic chromosome segregation" Nat. Commun. (2020) 10.1038/s41467-019-14009-0

[28]

Infante "Continuous transport of a small fraction of plasma membrane cholesterol to endoplasmic reticulum regulates total cellular cholesterol" eLife (2017) 10.7554/elife.25466

[29]

NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes

Rodney E. Infante, Michael L. Wang, Arun Radhakrishnan et al.

Proceedings of the National Academy of Sciences 2008 10.1073/pnas.0807328105

[30]

Israel "Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells" Nature (2012) 10.1038/nature10821

[31]

Ivanova "Altered mTOR signalling in nephropathic cystinosis" J. Inherit. Metab. Dis. (2016) 10.1007/s10545-016-9919-z

[32]

Jia "Galectin-3 coordinates a cellular system for lysosomal repair and removal" Dev. Cell (2020) 10.1016/j.devcel.2019.10.025

[33]

Jin "Mitochondrial membrane potential regulates PINK1 import and proteolytic destabilization by PARL" J. Cell Biol. (2010) 10.1083/jcb.201008084

[34]

Kane "PINK1 phosphorylates ubiquitin to activate Parkin E3 ubiquitin ligase activity" J. Cell Biol. (2014) 10.1083/jcb.201402104

[35]

Kazlauskaite "Parkin is activated by PINK1-dependent phosphorylation of ubiquitin at Ser65" Biochem. J. (2014) 10.1042/bj20140334

[36]

Kennedy "Adaptations of energy metabolism associated with increased levels of mitochondrial cholesterol in Niemann-Pick type C1-deficient cells" J. Biol. Chem. (2014) 10.1074/jbc.m114.559914

[37]

Khaminets "Ubiquitin-dependent and independent signals in selective autophagy" Trends Cell Biol. (2016) 10.1016/j.tcb.2015.08.010

[38]

AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1

Joungmok Kim, Mondira Kundu, Benoit Viollet et al.

Nature Cell Biology 2011 10.1038/ncb2152

[39]

Kobayashi "Late endosomal membranes rich in lysobisphosphatidic acid regulate cholesterol transport" Nat. Cell Biol. (1999) 10.1038/10084

[40]

Structure of N-Terminal Domain of NPC1 Reveals Distinct Subdomains for Binding and Transfer of Cholesterol

Hyock Joo Kwon, Lina Abi-Mosleh, Michael L. Wang et al.

Cell 2009 10.1016/j.cell.2009.03.049

[41]

Lamming "Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity" Science (2012) 10.1126/science.1215135

[42]

Lawrence "The lysosome as a cellular centre for signalling, metabolism and quality control" Nat. Cell Biol. (2019) 10.1038/s41556-018-0244-7

[43]

Lazarou "The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy" Nature (2015) 10.1038/nature14893

[44]

Li "Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis" Proc. Natl. Acad. Sci. USA (2010) 10.1073/pnas.0914798107

[45]

Li "Clues to the mechanism of cholesterol transfer from the structure of NPC1 middle lumenal domain bound to NPC2" Proc. Natl. Acad. Sci. USA (2016) 10.1073/pnas.1611956113

[46]

Lim "ER-lysosome contacts enable cholesterol sensing by mTORC1 and drive aberrant growth signalling in Niemann-Pick type C" Nat. Cell Biol. (2019) 10.1038/s41556-019-0391-5

[47]

Liu "Fbxo2 mediates clearance of damaged lysosomes and modifies neurodegeneration in the Niemann-Pick C brain" JCI Insight (2020) 10.1172/jci.insight.136676

[48]

Liu "mTOR at the nexus of nutrition, growth, ageing and disease" Nat. Rev. Mol. Cell Biol. (2020) 10.1038/s41580-019-0199-y

[49]

Loftus "Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene" Science (1997) 10.1126/science.277.5323.232

[50]

Lu "Identification of NPC1 as the target of U18666A, an inhibitor of lysosomal cholesterol export and Ebola infection" eLife (2015) 10.7554/elife.12177

Showing 50 of 101 references

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Metrics

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References

Details

Published: Feb 01, 2021
Vol/Issue: 56(3)
Pages: 260-276.e7
License: View

Authors

Whitehead Institute for Biomedical Research, Nine Cambridge Center; Cambridge MA USA; Department of Biology, Massachusetts Institute of Technology (MIT); Cambridge MA USA; David H Koch Institute for Integrative Cancer Research at MIT; Cambridge MA USA

Funding

National Institutes of Health

Cite This Article

Oliver B. Davis, Hijai R. Shin, Chun-Yan Lim, et al. (2021). NPC1-mTORC1 Signaling Couples Cholesterol Sensing to Organelle Homeostasis and Is a Targetable Pathway in Niemann-Pick Type C. Developmental Cell, 56(3), 260-276.e7. https://doi.org/10.1016/j.devcel.2020.11.016

NPC1-mTORC1 Signaling Couples Cholesterol Sensing to Organelle Homeostasis and Is a Targetable Pathway in Niemann-Pick Type C

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