title: Divergent signaling via SUMO modification: potential for CFTR modulation.
abstract: The cystic fibrosis transmembrane conductance regulator (CFTR) is generally responsible for the cAMP/PKA regulated anion conductance at the apical membranes of secretory epithelial cells. Mutations in CFTR underlie cystic fibrosis (CF), in which the most common variant, F508del, causes protein misfolding and its proteasome-mediated degradation. A new pathway that contributes to mutant CFTR degradation is mediated by the small heat shock protein, Hsp27, which cooperates with Ubc9, the E2 enzyme for SUMOylation, to selectively conjugate mutant CFTR with SUMO-2/3. This SUMO paralog can form polychains, which are recognized by the ubiquitin E3 enzyme, RNF4, leading to CFTR ubiquitylation and recognition by the proteasome. We found also that F508del CFTR could be modified by SUMO-1, a paralog that does not support SUMO polychain formation. The use of different SUMO paralogs to modify and target a single substrate for divergent purposes is not uncommon. In this short review we discuss the possibility that conjugation with SUMO-1 could protect mutant CFTR from disposal by RNF4 and similar ubiquitin ligases. We hypothesize that such a pathway could contribute to therapeutic efforts to stabilize immature mutant CFTR and thereby enhance the action of therapeutics that correct CFTR trafficking to the apical membranes.
authors.affiliation: Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Annette
authors.initials: A
authors.lastname: Ahner
authors.affiliation: Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Gong
authors.affiliation: Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Frizzell
mesh_terms: D000818:Animals; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D020545:Respiratory Mucosa / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000378:metabolism*; D058207:Sumoylation; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C505032:CFTR protein, human; D009687:Nuclear Proteins; C114070:RNF4 protein, human; D025842:SUMO-1 Protein; D014157:Transcription Factors; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D046988:Proteasome Endopeptidase Complex
keywords: SIM (SUMO-interacting motif); SUMO ligase; SUMO-specific peptidase; Ubc9 (SUMO-conjugating enzyme), multi-SUMOylation