Cystic fibrosis transmembrane conductance regulator degradation: cross‐talk between the ubiquitylation and SUMOylation pathways

Defining the significant checkpoints in cystic fibrosis transmembrane conductance regulator (CFTR) biogenesis should identify targets for therapeutic intervention with CFTR folding mutants such as F508del. Although the role of ubiquitylation and the ubiquitin proteasome system is well established in the degradation of this common CFTR mutant, the part played by SUMOylation is a novel aspect of CFTR biogenesis/quality control. We identified this post‐translational modification of CFTR as resulting from its interaction with small heat shock proteins (Hsps), which were found to selectively facilitate the degradation of F508del through a physical interaction with the SUMO (small ubiquitin‐like modifier) E2 enzyme, Ubc9. Hsp27 promoted the SUMOylation of mutant CFTR by the SUMO‐2 paralogue, which can form poly‐chains. Poly‐SUMO chains are then recognized by the SUMO‐targeted ubiquitin ligase, RNF4, which elicited F508del degradation in a Hsp27‐dependent manner. This work identifies a sequential connection between the SUMO and ubiquitin modifications of the CFTR mutant: Hsp27‐mediated SUMO‐2 modification, followed by ubiquitylation via RNF4 and degradation of the mutant via the proteasome. Other examples of the intricate cross‐talk between the SUMO and ubiquitin pathways are discussed with reference to other substrates; many of these are competitive and lead to different outcomes. It is reasonable to anticipate that further research on SUMO–ubiquitin pathway interactions will identify additional layers of complexity in the process of CFTR biogenesis and quality control. SUMOylation is a novel post‐translational modification of CFTR, mediated by selective interaction of the common mutant, F508del, with the small heat shock protein, Hsp27 and the SUMO E2, Ubc9. Cross‐talk with the ubiquitin pathway derives from the conjugation of F508del with SUMO‐2/3 poly‐chains that are recognized by the SUMO‐targeted ubiquitin ligase, RNF4. Other examples of SUMO‐ubiquitin pathway interactions are discussed.