Gergely L. Lukacs - Professor

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

Positions Available: Undergaduate,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.

Education:  M.D., Semmelweis Medical School, Budapest, Hungary Ph.D., Semmelweis Medical School, Budapest , Hungary Postdoctoral training: Dept. Pahrmacology and Physiology, Yale Medical School and University of Toronto and Hospital for Sick Children Research Institute

Recent Publications:

Valentine CD, Lukacs GL, Verkman AS, Haggie PM. Reduced PDZ Interactions of Rescued {Delta}F508CFTR Increases its Cell Surface Mobility. J Biol Chem 2012 Oct 31. [Epub ahead of print]

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

Guido Veit, Florian Bossard, A. S. Verkman, Luis J.V. Galietta, J. Hanrahan and GL Lukacs, Enhanced interleukin-8 secretion is suppressed by TMEM16A or CFTR channel activity in human cystic fibrosis bronchial epithelia, Mol Biol Cell, 2012, 23:4188-202

John T. Fisher, Xi Liu, Z Yan, M Luo, Y Zhang, W Zhou, BJ Lee, Y Song, C Guo, Y Wang, GL. Lukacs, and John F. Engelhardt, Comparative Processing and Function of the Human and Ferret Cystic Fibrosis Transmembrane Conductance Regulator, J Biol Chem, 2012, 287:21673-85

Lukacs GL and AS Verkman, CFTR: folding, misfolding, and correcting the ΔF508 conformational defect, Trends Mol Med, 2012, 8:81-91

Wael M. Rabeh, Florian Bossard, Haijin Xu, Tsukasa Okiyoneda, Miklos Bagdany, Cory M. Mulvihill, Kai Du, Salvatore di Bernardo, Yuhong Liu, Lars Konermann, Ariel Roldan, GL Lukacs, Correction of both NBD1 energetics and domain interface is required to restore ∆F508 CFTR folding and function, Cell 2012, 148:150-63.

Phuan PW, Yang B, Knapp J, Wood A, Lukacs GL, Kurth MJ, Verkman AS. Cyanoquinolineswith Independent Corrector and Potentiator Activities Restore delF508-CFTR Chloride Channel Function in Cystic Fibrosis. Mol Pharmacol 2011 80:683-93.

Okiyoneda, T., Apaja P and Lukacs GL, Protein Quality Control at the Plasma Membrane. Curr Opin Cell Biol., 2011 23 483-491  

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

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. recommended by Faculty 1000.

Barriere, H, Bagdany M, Bossard F, Wojewodka G, Gruenert D, Radzioch D and Lukacs GL Revisiting the role of CFTR and counterion permeability in the pH regulation of endocytic organelles, submitted, Mol Biol Cell, 2009, 20:3125-41

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, 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

Du K and Lukacs GL, Cooperative assembly and misfolding of CFTR domains in vivo. Mol Biol Cell, 2009, 20: 1903-1915, recommended by Faculty 1000.

Barriere, H, Nemes, C, Pampinella, F and Lukacs, GL, Plasticity of oligoubiquitin recognition by the endosomal sorting machinery as lysosomal targeting signal, Mol Biol Cell. 2007, 18:3952-65.

Traub, ML and Lukacs, GL, Decoding ubiquitin sorting signals for clathrin-dependent endocytosis by CLASPs, J. Cell Science, 2007, 120:543-553

H, Barriere, Nemes, C., Lechardeur, Kahn-Mohammad, M., Fruh, K. and GL Lukacs The molecular basis of oligoubiquitin-dependent internalization of membrane proteins in mammalian cells, Traffic (2006) 7: 282-297. Comments: I Madshus, Ubiquitin Binding in Endocytosis, Traffic (2006) 7: 258-261

N. Pedemonte, GL Lukacs, K Du, E Caci, O Zegarra-Moran, LJV Galietta and AS Verkman, Small molecule correctors of defective ∆F508-CFTR cellular processing identified by high-throughput screening, J. Clin. Invest. (2005) 115, 2564-2571

Du, K., Sharma, M. and Lukacs, GL, The ∆F508 cystic fibrosis mutation impairs domain-domain interactions and arrests posttranslational folding of CFTR, Nature Struct. Mol. Biol., (2005), 12, 17-25, Comments in News and Views, Nature Struct. Mol. Biol., (2005) 12, 2-3Mei Y.C, Partridge, A.W., Daniels, C., Du, K., Lukacs, GL and Deber, C.M., Destabilization of local hydrophobic character induces misfolding in a phenotypic mutant of the CFTR transmembrane domain. J. Biol. Chem., 2005, 280, 4968-4974

Lechardeur D, Ming X., and Lukacs GL, Nuclear dynamics of the caspase-activated DNase (CAD) in normal and apoptotic cells, J. Cell Biol. (2004) 167, 851-86  

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

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

Benharouga M, Sharma M, So J, Haardt M, Drzymala L, Popov M, Schwapach B, Grinstein S, Du K, and Lukacs GL; The role of the C-terminus and Na+/H+ exchanger regulatory factor (NHERF) in the functional expression of CFTR in non-polarized cells and epithelia, submitted to J. Biol. Chem. (2003) 278, 22079-2208

Sharma, M., Benharouga, M., Wei H. and Lukacs, GL, Conformational and temperature-sensitive stability defect of the ∆F508 cystic fibrosis transmembrane conductance regulator (CFTR) in post-endoplasmic reticulum compartment, J. Biol. Chem. (2001) 276:8942-8950

Benharouga, M, Haardt M, Kartner N and Lukacs GL, Carboxyl-terminal truncations promote proteasome-dependent degradation of mature CFTR from post-Golgi compartments, J. Cell Biol. (2001), 153, 957-970, featured Comments: J. Cell Biol, 2001, 153/5

Lechardeur D, Drzymala L, Sharma M, Zylka D, Kinach R, Pacia J, Hicks C, Usmani N, Rommens J and Lukacs GL, Determinants of the Nuclear Localization of the Heterodimeric DNA Fragmentation Factor (ICAD/CAD), J. Cell Biology (2000) 150, 321-334

Haardt M, Benharouga M, Lechardeur D, Kartner N and Lukacs GL, C-terminus Truncations Destabilize the Cystic Fibrosis Transmembrane Conductance Regulator without Impairing Its Biogenesis, J. BioI. Chem. (1999) 274,21873-21877

Zhang F, Kartner N and Lukacs GL, Limited Proteolysis as a Probe for the Arrested Conformational Maturation of the ∆F508 CFTR, Nature Struct. Biol., (1998) 5(3), 180-183

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