Chan Lab: Autophagy stress response

About our Research

We are interested in understanding how a cell adapts its metabolic pathways in response to external stress. The model that we focus on is the autophagy degradative pathway in mammalian cells.

During autophagy, cellular membranes form from the endoplasmic reticulum and elongate to capture cytoplasmic targets including proteins, mitochondria or foreign bacteria. This cargo capture can be non-specific or directed via ubiquitin-binding adaptor proteins that recognise components tagged for degradation. Our focus has long been the autophagy regulatory complex centered around ULK1 and ULK2, which also includes ATG13, ATG101 and FIP200. The ULK1/2 complex functions at the earliest stage of the autophagy signalling cascade and receives upstream signals from the nutrient sensors MTOR complex 1 (MTORC1) and AMPK. ULK1 thus serves as a central node that combines multiple nutrient sensing pathways from the lysosome and cytoplasm to autophagy.

Cancer cells are distinct for their re-programmed metabolic profile that features high catabolism of glucose and amino acids. Therefore, we have long been interested in the mechanisms linking amino acid and glucose sensing to autophagy.

We are currently looking for new Graduate students for Fall 2021

1. Coordination of mitochondrial fusion, autophagy and cellular metabolism

Mitochondria constantly undergo cycles of fission to generate smaller organelles, counterbalanced by fusion, which forms larger interconnected networks. Fusion has been also shown to be an adaptive response to nutrient starvation or proteostasis imbalance, thereby generating mitochondrial networks that escape degradation by autophagy. Mitochondrial fusion is associated with maintenance of metabolic fitness by minimizing effects of mtDNA mutation and protein damage. We are currently investigating the metabolic plasticity of mitochondria in an effort to understand the signalling mechanisms that coordinate nutrient starvation, mitochondrial fusion and autophagy.

2. Modulation of the Autophagy anti-bacterial response

Autophagy is important for host cell-pathogen interactions during bacterial infection. In this way, autophagy can degrade and restrict the replication of certain types of invading bacteria. On the other hand, we found that autophagy can be hijacked when cells are infected by pathogenic Staphylococcus aureus. Part of this autophagy subversion involves recruitment of the ULK1 complex to help generate a membrane enclosed intracellular niche to enable bacterial replication. Blocking ULK1 using inhibitors was able to stop Staphylococcus aureus infection. We are now developing further novel approaches for blocking the formation of the intracellular bacterial niche.

Karen Run Xeng: Masters student in Biochemistry: Nutrient dependent regulation of Mitochondrial Hyperfusion.

Chelsea Margerum: Masters student in Biochemistry: Modulating mitophagy and mitochondrial dynamics in breast cancer

Recently completed students

Mahmud Abdullah: PhD project: Coordination of mitophagy and mitochondrial dynamics in response to nutrient sensing.

Ohood Radhi: PhD project: ULK1-mediated Xenophagy following infection by methicillin-resistant Staphylococcus aureus.

Chinwe Nwadike: PhD project: Regulation of the ULK1 complex by metabolic starvation stress.

Yuming Shao: Queen's Biochemistry Thesis project: Metabolic reprogramming via inhibition of TCA cycle flux

Autumn Maracle: Queen's Life Science Thesis project: Metabolic reprogramming by mitochondrial dynamics

Leon Williamson: PhD project: Regulation of autophagy by non-canonical ULK1 signalling.

Laura Gallagher: PhD project: Targeting the Pro-survival role of autophagy in breast cancer

Martin Werno: PhD project: (Primary supervisor: Luke Chamberlain, University of Strathclyde) Protein palmltoylation in adipocytes: Role in insulin action

Rebecca Mitchell: PhD project: (Primary supervisors: Gudmundur Helgason, Tessa Holyoake, University of Glasgow) Role of autophagy during tyrosine kinase inhibitor resistance in Chronic myelogenous leukemia

Scott Davidson: Masters project: Role of autophagy for methicillin-resistant Stephylococcus aureus (MRSA) infection

Catriona Crossan: Masters project: Autophagy dependence on Stephylococcus aureus clonal complex group

Raul Berrocal Martin: Masters project: Roles of NRBP family members for regulation of the autophagy/lysosomal pathway

Mayumbe Chaplin: Masters project: Targeting autophagy for improving stem cell function in brain repair

Ross Kerr: Masters project: Protein acylation in autophagy regulation

Oluwafolabomi Shonubi: Masters project: Characterisation of novel kinases regulating autophagy

10K Tenovus Fun Run

Pub Day: Bubble and squeak £9.25

Ben having fun on Lab Exchange from Hamburg: Studies on ROCK1 function in autophagy

Ana: ERASMUS exchange from University of Porto: Oncolytic viral targetting of Ovarian Cancer cells

Life in the lab: we rely on protein biochemistry to study cell function.

We use molecular biology to target function or add fluorescent tags to proteins for further study

Cell imaging and microscopy are main approaches to our work.

From image data, we are able to gain a lot of qualitative and quantitative information on events inside of cells

Towards future studies, we are searching for new regulatory factors using genome wide screens

Abdullah, M. O., Zeng, R. X. Al-Rofaidi, M. Al-Tannak, N.F., Rattray, N.J.W., Eskelinen, E.L., Watson, D.G., Chan, E. Y. W. Mitochondrial hyperfusion via metabolic sensing of regulatory amino acids. (under revision)

https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3732407

Klionsky, D. J., et al. (2021). Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition). Autophagy, 17, 1-382.

https://doi.org/10.1080/15548627.2020.1797280

Grenier-Pleau, I., Tyryshkin, K., Le, T.D., Rudan, J., Bonneil, E., Thibault, P., Zeng, K., Lässer, C., Mallinson, D., Lamprou, D., Hui, J., Postovit, L.M., Chan, E.Y.W. and Abraham, S.A. (2020). Blood extracellular vesicles from healthy individuals regulate hematopoietic stem cells as humans age. Aging Cell, 19:e13245.

https://doi.org/10.1111/acel.13245

Radhi, O. A., S. Davidson, F. Scott, R. X. Zeng, D. H. Jones, N. C. O. Tomkinson, J. Yu, and E. Y. W. Chan. (2019) Inhibition of the Ulk1 Protein Complex Suppresses Staphylococcus-Induced Autophagy and Cell Death. J Biol Chem. http://dx.doi.org/10.1074/jbc.RA119.008923.

Anwar, T., X. Liu, T. Suntio, A. Marjamaki, J. Biazik, E. Y. W. Chan, M. Varjosalo, and E. L. Eskelinen. (2019) Er-Targeted Beclin 1 Supports Autophagosome Biogenesis in the Absence of Ulk1 and Ulk2 Kinases. Cells 8. http://dx.doi.org/10.3390/cells8050475.

Nwadike, C., L. E. Williamson, L. E. Gallagher, J. L. Guan, and E. Y. W. Chan. (2018) Ampk Inhibits Ulk1-Dependent Autophagosome Formation and Lysosomal Acidification Via Distinct Mechanisms. Mol Cell Biol 38. http://dx.doi.org/10.1128/MCB.00023-18.

Mitchell, R., L. E. M. Hopcroft, P. Baquero, E. K. Allan, K. Hewit, D. James, G. Hamilton, A. Mukhopadhyay, J. O'Prey, A. Hair, J. V. Melo, E. Chan, K. M. Ryan, V. Maguer-Satta, B. J. Druker, R. E. Clark, S. Mitra, P. Herzyk, F. E. Nicolini, P. Salomoni, E. Shanks, B. Calabretta, T. L. Holyoake, and G. V. Helgason. (2018) Targeting Bcr-Abl-Independent Tki Resistance in Chronic Myeloid Leukemia by Mtor and Autophagy Inhibition. J Natl Cancer Inst 110: 467-78. http://dx.doi.org/10.1093/jnci/djx236.

Gallagher, L. E., O. A. Radhi, M. O. Abdullah, A. G. McCluskey, M. Boyd, and E. Y. W. Chan. (2017) Lysosomotropism Depends on Glucose: A Chloroquine Resistance Mechanism. Cell Death Dis 8: e3014. http://dx.doi.org/10.1038/cddis.2017.416.

Karvela, M., P. Baquero, E. M. Kuntz, A. Mukhopadhyay, R. Mitchell, E. K. Allan, E. Chan, K. R. Kranc, B. Calabretta, P. Salomoni, E. Gottlieb, T. L. Holyoake, and G. V. Helgason. (2016) Atg7 Regulates Energy Metabolism, Differentiation and Survival of Philadelphia-Chromosome-Positive Cells. Autophagy 12: 936-48. http://dx.doi.org/10.1080/15548627.2016.1162359.

Gallagher, Laura, Leon Williamson, and Edmond Chan. (2016) Advances in Autophagy Regulatory Mechanisms. Cells 5: 24. http://dx.doi.org/10.3390/cells5020024.

Klionsky, D. J., et al. (2016) Guidelines for the Use and Interpretation of Assays for Monitoring Autophagy (3rd Edition). Autophagy 12: 1-222. http://dx.doi.org/10.1080/15548627.2015.1100356.

Watson, D. G., F. Tonelli, M. Alossaimi, L. Williamson, E. Chan, I. Gorshkova, E. Berdyshev, R. Bittman, N. J. Pyne, and S. Pyne. (2013) The Roles of Sphingosine Kinases 1 and 2 in Regulating the Warburg Effect in Prostate Cancer Cells. Cell Signal 25: 1011-7. http://dx.doi.org/10.1016/j.cellsig.2013.01.002.

Tonelli, F., M. Alossaimi, L. Williamson, R. J. Tate, D. G. Watson, E. Chan, R. Bittman, N. J. Pyne, and S. Pyne. (2013) The Sphingosine Kinase Inhibitor 2-(P-Hyroxyanilino)-4-(P-Chlorophenyl)Thiazole Reduces Androgen Receptor Expression Via an Oxidative Stress-Dependent Mechanism. Br J Pharmacol 168: 1497-505. http://dx.doi.org/10.1111/bph.12035.

Mleczak, A., S. Millar, S. A. Tooze, M. F. Olson, and E. Y. Chan. (2013) Regulation of Autophagosome Formation by Rho Kinase. Cell Signal 25: 1-11. http://dx.doi.org/10.1016/j.cellsig.2012.09.010.

McAlpine, F., L. E. Williamson, S. A. Tooze, and E. Y. Chan. (2013) Regulation of Nutrient-Sensitive Autophagy by Uncoordinated 51-Like Kinases 1 and 2. Autophagy 9: 361-73. http://dx.doi.org/10.4161/auto.23066.

Gallagher, L. E. and E. Y. Chan. (2013) Early Signalling Events of Autophagy. Essays Biochem 55: 1-15. http://dx.doi.org/10.1042/bse0550001.

Klionsky, D. J., et al. (2012) Guidelines for the Use and Interpretation of Assays for Monitoring Autophagy. Autophagy 8: 445-544.

Chan, E. Y. (2012) Regulation and Function of Uncoordinated-51 Like Kinase Proteins. Antioxid Redox Signal 17: 775-85. http://dx.doi.org/10.1089/ars.2011.4396.

Razi, M., E. Y. Chan, and S. A. Tooze. (2009) Early Endosomes and Endosomal Coatomer Are Required for Autophagy. J Cell Biol 185: 305-21. http://dx.doi.org/10.1083/jcb.200810098.

Chan, E. Y. and S. A. Tooze. (2009) Evolution of Atg1 Function and Regulation. Autophagy 5: 758-65. https://www.ncbi.nlm.nih.gov/pubmed/19411825.

Chan, E. Y., A. Longatti, N. C. McKnight, and S. A. Tooze. (2009) Kinase-Inactivated Ulk Proteins Inhibit Autophagy Via Their Conserved C-Terminal Domains Using an Atg13-Independent Mechanism. Mol Cell Biol 29: 157-71. http://dx.doi.org/10.1128/MCB.01082-08.

Chan, E. Y. (2009) Mtorc1 Phosphorylates the Ulk1-Matg13-Fip200 Autophagy Regulatory Complex. Sci Signal 2: pe51. http://dx.doi.org/10.1126/scisignal.284pe51.

Chan, E. Y., S. Kir, and S. A. Tooze. (2007) Sirna Screening of the Kinome Identifies Ulk1 as a Multidomain Modulator of Autophagy. J Biol Chem 282: 25464-74. http://dx.doi.org/10.1074/jbc.M703663200.

Young, A. R., E. Y. Chan, X. W. Hu, R. Kochl, S. G. Crawshaw, S. High, D. W. Hailey, J. Lippincott-Schwartz, and S. A. Tooze. (2006) Starvation and Ulk1-Dependent Cycling of Mammalian Atg9 between the Tgn and Endosomes. J Cell Sci 119: 3888-900. http://dx.doi.org/10.1242/jcs.03172.

Kochl, R., X. W. Hu, E. Y. Chan, and S. A. Tooze. (2006) Microtubules Facilitate Autophagosome Formation and Fusion of Autophagosomes with Endosomes. Traffic 7: 129-45. http://dx.doi.org/10.1111/j.1600-0854.2005.00368.x.

Warby, S. C., E. Y. Chan, M. Metzler, L. Gan, R. R. Singaraja, S. F. Crocker, H. A. Robertson, and M. R. Hayden. (2005) Huntingtin Phosphorylation on Serine 421 Is Significantly Reduced in the Striatum and by Polyglutamine Expansion in Vivo. Hum Mol Genet 14: 1569-77. http://dx.doi.org/10.1093/hmg/ddi165.

Tang, T. S., H. Tu, P. C. Orban, E. Y. Chan, M. R. Hayden, and I. Bezprozvanny. (2004) Hap1 Facilitates Effects of Mutant Huntingtin on Inositol 1,4,5-Trisphosphate-Induced Ca Release in Primary Culture of Striatal Medium Spiny Neurons. Eur J Neurosci 20: 1779-87. http://dx.doi.org/10.1111/j.1460-9568.2004.03633.x.

Tang, T. S., H. Tu, E. Y. Chan, A. Maximov, Z. Wang, C. L. Wellington, M. R. Hayden, and I. Bezprozvanny. (2003) Huntingtin and Huntingtin-Associated Protein 1 Influence Neuronal Calcium Signaling Mediated by Inositol-(1,4,5) Triphosphate Receptor Type 1. Neuron 39: 227-39.

Luthi-Carter, R., S. A. Hanson, A. D. Strand, D. A. Bergstrom, W. Chun, N. L. Peters, A. M. Woods, E. Y. Chan, C. Kooperberg, D. Krainc, A. B. Young, S. J. Tapscott, and J. M. Olson. (2002) Dysregulation of Gene Expression in the R6/2 Model of Polyglutamine Disease: Parallel Changes in Muscle and Brain. Hum Mol Genet 11: 1911-26.

Chan, E. Y., S. L. Stang, D. A. Bottorff, and J. C. Stone. (2002) Mutations in Conserved Regions 1, 2, and 3 of Raf-1 That Activate Transforming Activity. Mol Carcinog 33: 189-97.

Chan, E. Y., J. Nasir, C. A. Gutekunst, S. Coleman, A. Maclean, A. Maas, M. Metzler, M. Gertsenstein, C. A. Ross, A. Nagy, and M. R. Hayden. (2002) Targeted Disruption of Huntingtin-Associated Protein-1 (Hap1) Results in Postnatal Death Due to Depressed Feeding Behavior. Hum Mol Genet 11: 945-59.

Chan, E. Y., R. Luthi-Carter, A. Strand, S. M. Solano, S. A. Hanson, M. M. DeJohn, C. Kooperberg, K. O. Chase, M. DiFiglia, A. B. Young, B. R. Leavitt, J. H. Cha, N. Aronin, M. R. Hayden, and J. M. Olson. (2002) Increased Huntingtin Protein Length Reduces the Number of Polyglutamine-Induced Gene Expression Changes in Mouse Models of Huntington's Disease. Hum Mol Genet 11: 1939-51.

Chan, E. Y. (2002) Hip1 as a Marker of Aggressive Prostate Cancer. Clin Genet 62: 372-5. http://dx.doi.org/10.1034/j.1399-0004.2002.620503_4.x.

Hanna, A. N., E. Y. Chan, J. Xu, J. C. Stone, and D. N. Brindley. (1999) A Novel Pathway for Tumor Necrosis Factor-Alpha and Ceramide Signaling Involving Sequential Activation of Tyrosine Kinase, P21(Ras), and Phosphatidylinositol 3-Kinase. J Biol Chem 274: 12722-9.

Chan, E. Y., S. L. Stang, D. A. Bottorff, and J. C. Stone. (1999) Hypothermic Stress Leads to Activation of Ras-Erk Signaling. J Clin Invest 103: 1337-44. http://dx.doi.org/10.1172/jci5474.

Ebinu, J. O., D. A. Bottorff, E. Y. Chan, S. L. Stang, R. J. Dunn, and J. C. Stone. (1998) Rasgrp, a Ras Guanyl Nucleotide- Releasing Protein with Calcium- and Diacylglycerol-Binding Motifs. Science 280: 1082-6.

Rusinol, A. E., E. Y. Chan, and J. E. Vance. (1993) Movement of Apolipoprotein B into the Lumen of Microsomes from Hepatocytes Is Disrupted in Membranes Enriched in Phosphatidylmonomethylethanolamine. J Biol Chem 268: 25168-75.

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