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Cystic fibrosis transmembrane conductance regulator degradation: cross‐talk between the ubiquitylation and SUMO ylation pathways
Author(s) -
Ahner Annette,
Gong Xiaoyan,
Frizzell Raymond A.
Publication year - 2013
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12415
Subject(s) - sumo protein , ubiquitin , ubiquitin ligase , cystic fibrosis transmembrane conductance regulator , biogenesis , microbiology and biotechnology , rnf4 , regulator , mutant , proteasome , chemistry , endoplasmic reticulum associated protein degradation , deubiquitinating enzyme , biology , biochemistry , transcription factor , zinc finger , gene
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 SUMO ylation 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 ( H sps), which were found to selectively facilitate the degradation of F 508del through a physical interaction with the SUMO (small ubiquitin‐like modifier) E 2 enzyme, U bc9. H sp27 promoted the SUMO ylation of mutant CFTR by the SUMO ‐2 paralogue, which can form poly‐chains. P oly‐ SUMO chains are then recognized by the SUMO ‐targeted ubiquitin ligase, RNF 4, which elicited F 508del degradation in a H sp27‐dependent manner. This work identifies a sequential connection between the SUMO and ubiquitin modifications of the CFTR mutant: H sp27‐mediated SUMO ‐2 modification, followed by ubiquitylation via RNF 4 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.