Major research fields
Membrane Protein Disease, Innate Immunity
Plasma membrane (PM) proteins including signaling receptors, ion channels and transporters play crucial roles in physiological functions of cells and organisms. Genetic and environmental stresses cause the defective expression of PM proteins that is associated with several human diseases such as cystic fibrosis (CF). The ultimate goal in our research is to elucidate the molecular and cellular mechanisms underlying the defective expression of PM proteins and to help develop novel therapeutic approaches for human diseases.
Right now, we focus on the CFTR chloride channel associated with CF, one of the most common genetic diseases in Caucasians. While the most common CFTR mutant in CF patients has the ability to function as a chloride channel, it is rapidly eliminated by proteolysis through cellular quality control systems including the PM quality control mechanism that we originally identified. We are interested in understanding the molecular and cellular mechanisms that limit the PM expression and stability of CFTR, and how these mechanisms are affected by genetic and environmental stresses. By combining molecular cell biological, genetic and biochemical approaches, we particularly aim to identify the molecular machineries responsible for the ubiquitination and degradation of CFTR that determine the PM channel level and could be attractive drug targets.
Major relevant publications
- 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 restores ΔF508-CFTR folding and function. Nat Chem Biol. 2013 Jul;9(7):444-54.
- Okiyoneda T, Lukacs GL. Fixing cystic fibrosis by correcting CFTR domain assembly. J Cell Biol. 2012 Oct 15;199(2):199-204.
- Rabeh WM, Bossard F, Xu H, Okiyoneda T, Bagdany M, Mulvihill CM, Du K, di Bernardo S, Liu Y, Konermann L, Roldan A, Lukacs GL. Correction of both NBD1 energetics and domain interface is required to restore ΔF508 CFTR folding and function. Cell. 2012 Jan 20;148(1-2):150-63.
- Okiyoneda T, Apaja PM, Lukacs GL. Protein quality control at the plasma membrane. Curr Opin Cell Biol. 2011 Aug;23(4):483-91.
- Okiyoneda T, Barrière H, Bagdány M, Rabeh WM, Du K, Höhfeld J, Young JC, Lukacs GL. Peripheral protein quality control removes unfolded CFTR from the plasma membrane. Science. 2010 Aug 13;329(5993):805-10.