Department of Physiology McGill University McIntyre Medical Sciences Building, Room 1006 3655 Promenade Sir William Osler Montréal, Québec H3G 1Y6 Tel: (514) 398-5582 (office) Tel: (514) 398-6190 (laboratory) gergely.lukacs [at] mcgill.ca

Research Area:Ìý Molecular cell biology, protein quality control and sorting

Positions Available: Undergraduate, graduate and postdoctoral scientist positions

Research Description:

The cystic fibrosis gene product, CFTR, is a multidomain, polytopic plasma membrane protein that belongs to the ATP-Binding Cassette transporter family. The chloride channel activity of CFTR is indispensable for normal transcellular salt and water transport in numerous organs (e.g. gastrointestinal tract, pancreas and sweat duct) and for the homeostasis of airway surface liquid layer. Our long-term goal is to elucidate the molecular and cellular basis of cystic fibrosis, one of the most prevalent genetic diseases in the Caucasian population, caused by mutations interfering with the folding, stability, activity and/or membrane trafficking of the channel. To achieve this goal, we utilize a combination of biochemical, biophysical, cell biological and genetic techniques. Another aspect of our inquiries is to gain insights into the recognition and elimination mechanism of non-native membrane proteins from post-ER/Golgi compartments in mammalian cells. The peripheral quality control of integral membrane proteins likely represents a fundamental protective mechanism against the accumulation of aggregation prone and toxic polypeptides that are generated by cellular stresses or mutations. Using conditionally misfolded model proteins, we aim at identifying the machinery responsible for the disposal of non-native plasma membrane proteins. The structural and biochemical basis of ubiquitin recognition as an endocytic and postendocytic sorting signal is also investigated.

·¡»å³Ü³¦²¹³Ù¾±´Ç²Ô:Ìý M.D., Semmelweis Medical School, Budapest, Hungary; Ph.D., Semmelweis Medical School, Budapest, Hungary. Postdoctoral training: Dept. of Pharmacology and Physiology, Yale Medical School and Hospital for Sick Children Research Institute, University of Toronto.

Selected publications:

Lechardeur D, Sohn K-J, Haardt M, Joshi PB, Monck M, Graham RW, Beatty B, Squire J, O'Brodovich H and Lukacs GL: Metabolic instability of plasmid DNA in the cytosol: a potential barrier to gene transfer, Gene Therapy, (1999) 6, 482-497

Sharma M, Pampinella F, Benharouga M, Nemes C, So J, Papsin B, Drzymala L, Popov M, Zherangue N, Stenmark H, and Lukacs GL; Misfolding diverts CFTR from recycling towards degradation: peripheral quality control by the endosomal sorting machinery, J Cell Biol 2004, 164, 923-933

Marie E. Egan, Marilyn Pearson, Scott A. Weiner, Vanathy Rajendran, Daniel Rubin, Judith Glöckner-Page, Susan Cann, Kai Du, Lukacs, GL and M.J. Caplan, Curcumin, a Major Constituent of Turmeric, Corrects Cystic Fibrosis Defects, Science 2004, 304, 600-603

Glozman R, Okiyoneda T, Mulvihill C, Rini J, Barriere H, and Lukacs GL, N-glycans are direct determinants of CFTR folding and stability in secretory and endocytic membrane traffic, J Cell Biol, 2009, 184: 847-862 (featured at Nature Functional Glycomics Gateway: N-glycans in protein folding: Operating unchaperoned; Functional Glycomics (08 April 2009) doi:10.1038/fg

Okiyoneda, T., Barriere, H., Bagdany, M., Rabeh^, W.M., Höhfeld, J., Young J., and Lukacs GL, Peripheral Protein Quality Control Removes Unfolded CFTR from the Plasma Membrane, Science, 2010, 329:805-810. Featured in Science, 2010, 329:766-67 and Nature 2010, 466: 162

Apaja P, Xu H, and Lukacs GL Quality control for unfolded proteins at the plasma membrane, J Cell Biol 2010, 191: 553-570

Rabeh W, Bossard F, Xu H, Okiyoneda T, Bagdany M, Mulvihill C, Du K, di Bernardo S, Liu Y, Konermann L, Roldan A, GL Lukacs, Correction of both NBD1 energetics and domain interface is required to restore ∆F508 CFTR folding and function, Cell 2012, 148:150-63. Featured: SciBX, 2012:5:1-3, cover story

T. Okiyoneda and Lukacs GL, Fixing cystic fibrosis by correcting CFTR domain assembly, J Cell Biol, 2012, 199:199-204.

Okiyoneda T, Veit G, Dekkers JF, Bagdany M, Soya N, Xu H, Roldan A, Verkman AS, Kurth M, Simon A, Hegedus T, Beekman JM, Lukacs GL, Mechanism-based corrector combination synergistically restores DF508-CFTR folding and function in cystic fibrosis, Nature Chem Biol, 2013, 9:444-54, Featured in Science Business Exchange (SciBX) 6(24)

Veit G, Avramescu R, Perdomo D, Phuan P-W, Bagdany M, Apaja PM, Borot F, Szollosi D, Finkbeiner WE, Hegedus T, Verkman AS, Lukacs GL, Opposing effects of the gating potentiator VX-770 on corrected ΔF508-CFTR activity and processing, Science Translational Med, 2014 Jul 23; 6(246):246ra97, featured in Science, Science Translational Medicine, Boston Globe, and Wall Street Journal.

Veit G, K Oliver, PM Apaja, D Perdomo, A Bidaud-Meynard, S-T Lin, J Guo, M Icyuz, EJ Sorscher, JL Hartman IV, Lukacs, GL, Ribosomal stalk protein silencing corrects the ΔF508-CFTR functional expression defect, PlosBiology, 2016 May 11;14(5):e1002462.

Bagdany M, Veit G, Tsukasa Okiyoneda, Imad Baaklini, Jay Singh, Guy Sovak, Haijin Xu, Pirjo M. Apaja, Ariel Roldan, William Balch, Jason C. Young, and Lukacs GL, Chaperones rescue the energetic landscape of mutant CFTR at single molecule and in cell, Nature Commun, 2017, 8 article number: 398 (2017) doi:10.1038/s41467-017-00444-4

Okiyoneda T, Veit G, Sakai R, Aki M, Susuki-Miyata S, Miyata M, Fukuda N, Yoshida A, Xu H, Apaja MP, Lukacs GL, Chaperone-independent peripheral quality control of CFTR by endosomal RFFL E3 ligase, Dev Cell, 2018 44:694-708.e7.

Sauvé V, Sung G, Soya N, Kozlov G, Blaimschein N, Miotto L, Trempe J-F, Lukacs GL, and Gehring K, Mechanism of parkin activation by phosphorylation, Nature Struct Mol Biol, 2018 25:623-630, featured by Le Guerroue F & Youle R, Active state of Parkin Nature Struct & Mol Biol 2018 25, 644–646

Brian Foo, Barbier C, Vasantharuban J, Lukacs GL, and Shrier A Mutation-specific ER and peripheral quality control of hERG channel cell-surface expression Sci Rep, 2019 Apr 15;9(1):6066. doi:10.1038/s41598-019-42331-6

Schnúr A, Premchandar A, Bagdany M, Lukacs GL. Phosphorylation-dependent modulation of CFTR macromolecular signaling complex activity by cigarette smoke condensate in airway epithelia Sci Rep. 2019 Sep 3;9(1):12706. doi: 10.1038/s41598-019-48971-y.

Veit G, Roldan A, Hancock MA, Da Fonte DF, Xu H, Hussein M, Frenkiel S, Matouk E, Velkov T, and Lukacs GL. Allosteric folding correction of F508del and rare CFTR mutants by elexacaftor-tezacaftor-ivacaftor (Trikafta) combination, JCI Insight 2020, Sep 17;5(18):e139983. doi: 10.1172/jci.insight.139983.

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