Ridgway, Neale - Dalhousie University - Department of Biochemistry & Molecular Biology

研究领域

Intracellular cholesterol transport pathways Cholesterol in low-density lipoproteins is deposited in artery walls leading to heart disease and stroke. This is counteracted by pathways that export cholesterol from cells to high density lipoprotein acceptors for eventual removal by the liver. Lipoproteins in the bloodstream are controlled at the cellular level by transcriptional and post-transcriptional regulatory circuits that interact with cholesterol or its oxygenated derivatives (oxysterols) in the endoplasmic reticulum, plasma membrane and nucleus to impart negative or positive feed-back regulation of cholesterol metabolism. Thus the signals coming from these regulatory pathways depend on the amount of cholesterol they encounter, which is in turn controlled by ill-defined cholesterol transport processes. We are identifying these cholesterol transport pathways by studying a family of high affinity cholesterol and oxysterol receptors called oxysterol binding proteins (OSBPs). OSBPs have sterol-binding domains, pleckstrin homology domains that bind phosphatidylinositol phosphates (PIPs) and a motif that binds a protein called VAP in the endoplasmic reticulum. This domain configuration allows OSBPs to interact with and transfer cholesterol between target organelles, such as the Golgi apparatus and endoplasmic reticulum. We are currently investigating how OSBP–mediated cholesterol and oxysterol transport affects cellular cholesterol homeostasis, with a specific focus on the role of OSBPs in cholesterol removal from cells and modulation of cholesterol levels in the secretory and endocytic pathways. Role of lipid synthesis in cell proliferation and apoptosis Phosphatidylcholine (PC), the major glycerophospholipid in eukaryotic cells, is a key constituent of membranes and a source of growth-regulating signaling molecules, such as diacylglycerol and phosphatidic acid. PtdCho synthesis is regulated by the activity of the rate-limiting, nuclear enzyme CTP:phosphocholine cytidylyltransferase (CCT). During apoptosis, CCT is proteolyzed by caspases and exported from the nucleus as a part of program that prevents further PC synthesis. On the other hand, cancer cells have elevated CCT expression and nuclear activity. We are currently investigating the pivotal role that CCT plays in cell survival, and whether it is required for evasion of apoptosis by cancer cells. CCT also regulates the architecture of nuclear membranes by physically interacting with the nuclear envelope and forming membrane invaginations into the interior of the nucleus called the nucleoplasmic reticulum (NR). The NR is a ‘hotspot’ for calcium signaling and enhances transport of material between the cytoplasm and nucleus. Currently we are investigating how the NR forms, its function(s), and pathological roles in cell transformation and carcinogenesis.

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Charman, M., Goto, A. N., Ridgway, N.D. , (2017) Oxysterol binding protein recruitment and activity at the ER-Golgi interface are independent of Sac1 Traffic In Press: [PubMed] Zhao, K., Ridgway N.D. , (2017) ORP1L regulates cholesterol egress from the endo-lysosomal system Cell Reports 19:1807-1809 [PubMed] Goto, A., Charman, M. and Ridgway N.D., (2016) Oxysterol Binding Protein Activation at Endoplasmic Reticulum-Golgi Contact Sites Reorganizes Phosphatidylinositol 4-Phosphate Pools J. Biol. Chem. 219:1336-1347 [PubMed] Ridgway, N.D., (2016) Analysis of sphingolipid synthesis and transport by metabolic labeling of cultured cells with [3H]serine Methods Mol. Biol. 1376:195-202 [PubMed] Maekawa, M., Lee, M., Wei, K., Ridgway, N.D., and Fairn, G.D. , (2016) Staurosporines decrease ORMDL proteins and enhance sphingomyelin synthesis resulting in depletion of plasmalemmal phosphatidylserine Sci Reports 6:35726 [PubMed] Aitchison, A.J., Arsenault, D.J., and Ridgway, N., (2015) Nuclear-localized CTP: phosphocholine cytidylyltransferase α regulates phosphatidylcholine synthesis required for lipid droplet biogenesis Mol. Biol. Cell 26(16):2927-2938 [PubMed] [Article] Ridgway , N.D. and McLeod, R.S., (2015) Biochemistry of Lipids, Lipoproteins and Membranes Editors: Ridgway and McLeod : [Article] Cornell, R.B. and Ridgway N.D., (2015) CTP: phosphocholine cytidylyltransferase: Function, regulation, and structure of an amphitropic enzyme required for membrane biogenesis. Prog. Lipid Res. 59:147-171 [PubMed] Liu, X. and Ridgway, N.D., (2014) Characterization of the sterol and phosphatidylinositol 4-phosphate binding properties of Golgi-associated OSBP-related protein 9 (ORP9) Plos One 9 (9):e108368: [PubMed] Charman, M., Colbourne, T.R., Pietrangelo, A., Kreplak, L., Ridgway, N.D., (2014) Oxysterol-binding protein (OSBP)-related protein 4 (ORP4) is essential for cell proliferation and survival J.Biol.Chem 289:15705-15804 [PubMed] Park, IW., Ndjomou, J., Wen, Y., Liu Z, Ridgway, ND., Kao, CC., He, JJ., (2013) Inhibition of HCV Replication by Oxysterol-Binding Protein-Related Protein 4 (ORP4) through Interaction with HCV NS5B and Alteration of Lipid Droplet Formation. PloS One 17:e75648 [PubMed] Arsenault DJ, Yoo BH, Rosen KV, Ridgway ND, (2013) ras-Induced up-regulation of CTP:phosphocholine cytidylyltransferase α contributes to malignant transformation of intestinal epithelial cells. J. Biol. Chem. 288:633-43 [PubMed] Lagace, T.A. and Ridgway, N.D. , (2013) The role of phospholipids in the biological activity of the endoplasmic reticulum Biochim. Biophys. ACTA 1833:2499-2510 [PubMed] Morton, C.C., Aitchison, A.J., Karsten, G. and and Ridgway, N.D., (2013) A mechanism for suppression of the CDP-choline pathway during apoptosis J. Lipid Res. 54:3373-3381 [PubMed] Ridgway, N.D., (2012) The role of phosphatidylcholine and choline metabolites in cell proliferation and survival Critical Reviews in Biochemistry and Molecular Biology 48:20-38 [PubMed] A. Goto, X. Liu, C. Robinson and N. Ridgway, (2012) Multi-Site Phosphorylation of Oxysterol Binding Protein (OSBP) Regulates Sterol Binding and Activation of Sphingomyelin Synthesis Mol. Biol. Cel 23:3624-3635 [PubMed] Ngo, M., Colbourne, T.R. and Ridgway, N.D. , (2010) The Functional Implications of Sterol Transport by the Oxysterol Binding Protein Gene Family Biochem. J. 429:13-24 [PubMed] Ridgway, N. D., (2010) Oxysterol binding proteins Subcell Biochem 51:159-182 [PubMed] Hilchie AL, Furlong SJ, Sutton K, Richardson A, Robichaud MR, Giacomantonio CA, Ridgway ND, Hoskin DW., (2010) Curcumin-induced apoptosis in PC3 prostate carcinoma cells is caspase-independent and involves cellular ceramide accumulation and damage to mitochondria. Nutr Cancer 62:379-389 [PubMed] Nhek S, Ngo M, Yang X, Ng MM, Field SJ, Asara JM, Ridgway ND, Toker A., (2010) Regulation of OSBP Golgi Localization through Protein Kinase D-mediated Phosphorylation. Mol Biol Cell 21:2327-2337 [PubMed] Banerji, S., Ngo, M., Lane, C.F., Robinson, C., Minogue, S., and Ridgway, N.D. , (2010) OSBP-dependent activation of sphingomyelin synthesis in the Golgi apparatus requires PtdIns 4-kianse II alpha Mol. Biol. Cell 21:4141-4150 [PubMed]