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The cholesterol transport protein GRAMD1C regulates autophagy initiation and mitochondrial bioenergetics

Ng, Matthew Yoke Wui, Charsou, Chara, Lapao, Ana, Singh, Sakshi, Trachsel-Moncho, Laura, Schultz, Sebastian W., Nakken, Sigve, Munson, Michael J., Simonsen, Anne·2022·Nature Communications
DOI 10.1038/s41467-022-33933-2PMC PMC9586981
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Abstract

During autophagy, cytosolic cargo is sequestered into double-membrane vesicles called autophagosomes. The contributions of specific lipids, such as cholesterol, to the membranes that form the autophagosome, remain to be fully characterized. Here, we demonstrate that short term cholesterol depletion leads to a rapid induction of autophagy and a corresponding increase in autophagy initiation events. We further show that the ER-localized cholesterol transport protein GRAMD1C functions as a negative regulator of starvation-induced autophagy and that both its cholesterol transport VASt domain and membrane binding GRAM domain are required for GRAMD1C-mediated suppression of autophagy initiation. Similar to its yeast orthologue, GRAMD1C associates with mitochondria through its GRAM domain. Cells lacking GRAMD1C or its VASt domain show increased mitochondrial cholesterol levels and mitochondrial oxidative phosphorylation, suggesting that GRAMD1C may facilitate cholesterol transfer at ER-mitochondria contact sites. Finally, we demonstrate that expression of GRAMD family proteins is linked to clear cell renal carcinoma survival, highlighting the pathophysiological relevance of cholesterol transport proteins.

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  1. Fengsrud, M., Erichsen, E. S., Berg, T. O., Raiborg, C. & Seglen, P. O. Ultrastructural characterization of the delimiting membranes of isolated autophagosomes and amphisomes by freeze-fracture electron microscopy. Eur. J. Cell Biol. 79, 871–882 (2000). · DOI · Paper page
  2. de la Ballina, L. R., Munson, M. J. & Simonsen, A. Lipids and lipid-binding proteins in selective autophagy. J. Mol. Biol. 432, 135–159 (2020). · DOI
  3. Laczkó-Dobos, H. et al. Lipid profiles of autophagic structures isolated from wild type and Atg2 mutant Drosophila. Biochimica et. Biophysica Acta (BBA) - Mol. Cell Biol. Lipids 1866, 158868 (2021). · DOI
  4. Schütter, M., Giavalisco, P., Brodesser, S. & Graef, M. Local fatty acid channeling into phospholipid synthesis drives phagophore expansion during autophagy. Cell 180, 135–149.e114 (2020). · DOI
  5. Ogasawara, Y. et al. Stearoyl-CoA desaturase 1 activity is required for autophagosome formation. J. Biol. Chem. 289, 23938–23950 (2014). · DOI
  6. Ogasawara, Y., Kira, S., Mukai, Y., Noda, T. & Yamamoto, A. Ole1, fatty acid desaturase, is required for Atg9 delivery and isolation membrane expansion during autophagy in Saccharomyces cerevisiae. Biol. Open 6, 35–40 (2017).
  7. Nath, S. et al. Lipidation of the LC3/GABARAP family of autophagy proteins relies on a membrane-curvature-sensing domain in Atg3. Nat. Cell Biol. 16, 415–424 (2014). · DOI
  8. London, E. & Brown, D. A. Insolubility of lipids in triton X-100: physical origin and relationship to sphingolipid/cholesterol membrane domains (rafts). Biochim Biophys Acta 1508, 182–195 (2000). · DOI
  9. Fernández-Pérez, E. J. et al. Effect of cholesterol on membrane fluidity and association of aβ oligomers and subsequent neuronal damage: a double-edged sword. Front. Aging Neurosci. 10, https://doi.org/10.3389/fnagi.2018.00226 (2018). · DOI
  10. Liao, Y., Zhang, P., Yuan, B., Li, L. & Bao, S. Pravastatin protects against avascular necrosis of femoral head via autophagy. Front Physiol. 9, 307–307 (2018). · DOI
  11. Wei, Y. M. et al. Enhancement of autophagy by simvastatin through inhibition of Rac1-mTOR signaling pathway in coronary arterial myocytes. Cell Physiol. Biochem. 31, 925–937 (2013). · DOI
  12. Gao, S. et al. Atorvastatin activates autophagy and promotes neurological function recovery after spinal cord injury. Neural Regen. Res 11, 977–982 (2016). · DOI
  13. Wang, W. et al. Augmentation of autophagy by atorvastatin via Akt/mTOR pathway in spontaneously hypertensive rats. Hypertension Res. 38, 813–820 (2015). · DOI
  14. Cheng, J., Ohsaki, Y., Tauchi-Sato, K., Fujita, A. & Fujimoto, T. Cholesterol depletion induces autophagy. Biochemical Biophysical Res. Commun. 351, 246–252 (2006). · DOI
  15. Naito, H. et al. High-fat and high-cholesterol diet decreases phosphorylated inositol-requiring kinase-1 and inhibits autophagy process in rat liver. Sci. Rep. 9, 12514 (2019). · DOI
  16. Li, K. et al. High cholesterol induces apoptosis and autophagy through the ROS-activated AKT/FOXO1 pathway in tendon-derived stem cells. Stem Cell Res. Ther. 11, 131 (2020). · DOI
  17. McFarland, A. J. et al. Differences in statin associated neuroprotection corresponds with either decreased production of IL-1β or TNF-α in an in vitro model of neuroinflammation-induced neurodegeneration. Toxicol. Appl. Pharmacol. 344, 56–73 (2018). · DOI
  18. Seo, Y.-K. et al. Genome-wide localization of SREBP-2 in hepatic chromatin predicts a role in autophagy. Cell Metab. 13, 367–375 (2011). · DOI
  19. Luo, J., Jiang, L.-Y., Yang, H. & Song, B.-L. Intracellular cholesterol transport by sterol transfer proteins at membrane contact sites. Trends Biochemical Sci. 44, 273–292 (2019). · DOI
  20. Wong, L. H., Gatta, A. T. & Levine, T. P. Lipid transfer proteins: the lipid commute via shuttles, bridges and tubes. Nat. Rev. Mol. Cell Biol. 20, 85–101 (2019). · DOI · Paper page
  21. Naito, T. et al. Movement of accessible plasma membrane cholesterol by the GRAMD1 lipid transfer protein complex. eLife 8, e51401 (2019). · DOI · Paper page
  22. Laraia, L. et al. The cholesterol transfer protein GRAMD1A regulates autophagosome biogenesis. Nat. Chem. Biol. 15, 710–720 (2019). · DOI
  23. Dai, S. et al. Methyl-β-cyclodextrin restores impaired autophagy flux in Niemann-Pick C1-deficient cells through activation of AMPK. Autophagy 13, 1435–1451 (2017). · DOI
  24. Liang, D. et al. Effects and mechanisms of autophagy induced by solubilized-cholesterol in hepatocytes: a comparative study among solvents. Cell Biochem. Biophysics 78, 357–366 (2020). · DOI
  25. Parikh, A. et al. Statin-induced autophagy by inhibition of geranylgeranyl biosynthesis in prostate cancer PC3 cells. Prostate 70, 971–981 (2010). · DOI
  26. Ohtani, Y., Irie, T., Uekama, K., Fukunaga, K. & Pitha, J. Differential effects of α-, β- and γ-cyclodextrins on human erythrocytes. Eur. J. Biochem. 186, 17–22 (1989). · DOI
  27. Davis, O. B. et al. NPC1-mTORC1 signaling couples cholesterol sensing to organelle homeostasis and is a targetable pathway in Niemann-Pick type C. Dev. Cell 56, 260–276.e267 (2021). · DOI · Paper page
  28. Puente, C., Hendrickson, R. C. & Jiang, X. Nutrient-regulated phosphorylation of ATG13 inhibits starvation-induced autophagy. J. Biol. Chem. 291, 6026–6035 (2016). · DOI
  29. Luhr, M., Sætre, F. & Engedal, N. The long-lived protein degradation assay: an efficient method for quantitative determination of the autophagic flux of endogenous proteins in adherent cell lines. Bio-Protoc. 8, e2836 (2018). · DOI · Paper page
  30. Munson, M. J. et al. GAK and PRKCD are positive regulators of PRKN-independent mitophagy. Nat. Commun. 12, 6101 (2021). · DOI
  31. Allen, G. F. G., Toth, R., James, J. & Ganley, I. G. Loss of iron triggers PINK1/Parkin-independent mitophagy. EMBO Rep. 14, 1127–1135 (2013). · DOI · Paper page
  32. Narendra, D., Tanaka, A., Suen, D.-F. & Youle, R. J. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J. Cell Biol. 183, 795–803 (2008). · DOI · Paper page
  33. Hurley, J. H. & Young, L. N. Mechanisms of autophagy initiation. Annu. Rev. Biochem. 86, 225–244 (2017). · DOI
  34. Besprozvannaya, M. et al. GRAM domain proteins specialize functionally distinct ER-PM contact sites in human cells. eLife 7, e31019 (2018). · DOI · Paper page
  35. Elbaz-Alon, Y. et al. Lam6 regulates the extent of contacts between organelles. Cell Rep. 12, 7–14 (2015). · DOI
  36. Hamasaki, M. et al. Autophagosomes form at ER–mitochondria contact sites. Nature 495, 389–393 (2013). · DOI · Paper page
  37. Maekawa, M. Domain 4 (D4) of perfringolysin O to visualize cholesterol in cellular membranes-the update. Sensors 17, 504 (2017). · DOI
  38. Khanna, P., Lee, J. S., Sereemaspun, A., Lee, H. & Baeg, G. H. GRAMD1B regulates cell migration in breast cancer cells through JAK/STAT and Akt signaling. Sci. Rep. 8, 9511 (2018). · DOI · Paper page
  39. Hao, H. et al. Reduced GRAMD1C expression correlates to poor prognosis and immune infiltrates in kidney renal clear cell carcinoma. PeerJ 7, e8205 (2019). · DOI
  40. Nabi, S., Kessler, E. R., Bernard, B., Flaig, T. W. & Lam, E. T. Renal cell carcinoma: a review of biology and pathophysiology. F1000Res 7, 307–307 (2018). · DOI
  41. Drabkin, H. A. & Gemmill, R. M. Cholesterol and the development of clear-cell renal carcinoma. Curr. Opin. Pharm. 12, 742–750 (2012). · DOI
  42. Creighton, C. J. et al. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499, 43–49 (2013). · DOI · Paper page
  43. Axe, E. L. et al. Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J. Cell Biol. 182, 685–701 (2008). · DOI · Paper page
  44. Andrejeva, G. et al. De novo phosphatidylcholine synthesis is required for autophagosome membrane formation and maintenance during autophagy. Autophagy 16, 1044–1060 (2020). · DOI
  45. Nishimura, T. et al. Autophagosome formation is initiated at phosphatidylinositol synthase-enriched ER subdomains. EMBO J. 36, 1719–1735 (2017). · DOI
  46. Osawa, T. et al. Atg2 mediates direct lipid transfer between membranes for autophagosome formation. Nat. Struct. Mol. Biol. 26, 281–288 (2019). · DOI
  47. Valverde, D. P. et al. ATG2 transports lipids to promote autophagosome biogenesis. J. Cell Biol. 218, 1787–1798 (2019). · DOI
  48. Matoba, K. et al. Atg9 is a lipid scramblase that mediates autophagosomal membrane expansion. Nat. Struct. Mol. Biol. 27, 1185–1193 (2020). · DOI · Paper page
  49. Andersen, J.-P. et al. Aster-B coordinates with Arf1 to regulate mitochondrial cholesterol transport. Mol. Metab. 42, 101055 (2020). · DOI
  50. Eisenberg-Bord, M., Shai, N., Schuldiner, M. & Bohnert, M. A tether is a tether is a tether: tethering at membrane contact sites. Dev. Cell 39, 395–409 (2016). · DOI
  51. Garofalo, T. et al. Evidence for the involvement of lipid rafts localized at the ER-mitochondria associated membranes in autophagosome formation. Autophagy 12, 917–935 (2016). · DOI
  52. Zhang, J. et al. Aster-C coordinates with COP I vesicles to regulate lysosomal trafficking and activation of mTORC1. EMBO Rep. 21, e49898 (2020). · DOI
  53. Nascimbeni, A. C. et al. ER-plasma membrane contact sites contribute to autophagosome biogenesis by regulation of local PI3P synthesis. EMBO J. 36, 2018–2033 (2017). · DOI
  54. Ge, L., Melville, D., Zhang, M. & Schekman, R. The ER–Golgi intermediate compartment is a key membrane source for the LC3 lipidation step of autophagosome biogenesis. eLife 2, e00947 (2013). · DOI
  55. Charman, M., Kennedy, B. E., Osborne, N. & Karten, B. MLN64 mediates egress of cholesterol from endosomes to mitochondria in the absence of functional Niemann-Pick Type C1 protein. J. Lipid Res. 51, 1023–1034 (2010). · DOI
  56. Solsona-Vilarrasa, E. et al. Cholesterol enrichment in liver mitochondria impairs oxidative phosphorylation and disrupts the assembly of respiratory supercomplexes. Redox Biol. 24, 101214–101214 (2019). · DOI
  57. Ziolkowski, W. et al. Methyl-beta-cyclodextrin induces mitochondrial cholesterol depletion and alters the mitochondrial structure and bioenergetics. FEBS Lett. 584, 4606–4610 (2010). · DOI
  58. Durhuus, J. A. et al. Simvastatin improves mitochondrial respiration in peripheral blood cells. Sci. Rep. 10, 17012 (2020). · DOI
  59. Griffiths, G. W. & Beck, S. D. Effect of dietary cholesterol on the pattern of osmium deposition in the symbiote-containing cells of the pea aphid. Cell Tissue Res. 176, 191–203 (1977). · DOI
  60. Gebhard, R. L. et al. Abnormal cholesterol metabolism in renal clear cell carcinoma. J. Lipid Res 28, 1177–1184 (1987). · DOI
  61. Tugnoli, V., Trinchero, A. & Tosi, M. R. Evaluation of the lipid composition of human healthy and neoplastic renal tissues. Ital. J. Biochem 53, 169–182 (2004).
  62. Orhon, I. et al. Primary-cilium-dependent autophagy controls epithelial cell volume in response to fluid flow. Nat. Cell Biol. 18, 657–667 (2016). · DOI
  63. Zemirli, N. et al. The primary cilium protein folliculin is part of the autophagy signaling pathway to regulate epithelial cell size in response to fluid flow. Cell Stress 3, 100–109 (2019). · DOI
  64. Patergnani, S. et al. The induction of AMPK-dependent autophagy leads to P53 degradation and affects cell growth and migration in kidney cancer cells. Exp. Cell Res 395, 112190 (2020). · DOI
  65. Li, D. et al. LncRNA HOTAIR induces sunitinib resistance in renal cancer by acting as a competing endogenous RNA to regulate autophagy of renal cells. Cancer Cell Int. 20, 338 (2020). · DOI
  66. Ward, R. J., Alvarez-Curto, E. & Milligan, G. In Receptor Signal Transduction Protocols: Third Edition (eds Gary B. Willars & R. A. John Challiss) 21–37 (Humana Press, 2011). · DOI
  67. Ran, F. A. et al. Genome engineering using the CRISPR-Cas9 system. Nat. Protoc. 8, 2281–2308 (2013). · DOI · Paper page
  68. Labun, K. et al. CHOPCHOP v3: expanding the CRISPR web toolbox beyond genome editing. Nucleic Acids Res. 47, W171–W174 (2019). · DOI
  69. McQuin, C. et al. CellProfiler 3.0: next-generation image processing for biology. PLoS Biol. 16, e2005970 (2018). · DOI
  70. Carpenter, A. E. et al. CellProfiler: image analysis software for identifying and quantifying cell phenotypes. Genome Biol. 7, R100 (2006). · DOI
  71. Chen, W. W., Freinkman, E. & Sabatini, D. M. Rapid immunopurification of mitochondria for metabolite profiling and absolute quantification of matrix metabolites. Nat. Protoc. 12, 2215–2231 (2017). · DOI
  72. Jones, T. R. et al. CellProfiler Analyst: data exploration and analysis software for complex image-based screens. BMC Bioinforma. 9, 482 (2008). · DOI
  73. Jones, T. R. et al. Scoring diverse cellular morphologies in image-based screens with iterative feedback and machine learning. Proc. Natl Acad. Sci. USA 106, 1826–1831 (2009). · DOI
  74. Cox, J. & Mann, M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat. Biotechnol. 26, 1367–1372 (2008). · DOI · Paper page
  75. Tyanova, S. et al. The Perseus computational platform for comprehensive analysis of (prote)omics data. Nat. Methods 13, 731–740 (2016). · DOI · Paper page
  76. Ritchie, M. E. et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47 (2015). · DOI · Paper page
  77. Ge, S. X., Jung, D. & Yao, R. ShinyGO: a graphical gene-set enrichment tool for animals and plants. Bioinformatics 36, 2628–2629 (2019). · DOI · Paper page
  78. Colaprico, A. et al. TCGAbiolinks: an R/Bioconductor package for integrative analysis of TCGA data. Nucleic Acids Res. 44, e71 (2016). · DOI
  79. Sievers, F. et al. Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol. Syst. Biol. 7, 539–539 (2011). · DOI
  80. Altschul, S. F., Gish, W., Miller, W., Myers, E. W. & Lipman, D. J. Basic local alignment search tool. J. Mol. Biol. 215, 403–410 (1990). · DOI · Paper page

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Metadata

Authors
Ng, M. Y. W., Charsou, C., Lapao, A., Singh, S., Trachsel-Moncho, L., Schultz, S. W., Nakken, S., Munson, M. J., & Simonsen, A.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-10-21
Volume
13
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-022-33933-2
PMC
PMC9586981
Cited by
59
References
11
Language
en
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