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Review
. 2013 Sep;280(18):4430-8.
doi: 10.1111/febs.12415. Epub 2013 Jul 22.

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

Annette Ahner  1 , Xiaoyan Gong, Raymond A Frizzell
Affiliations
Review

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

Annette Ahner et al. FEBS J. 2013 Sep.

Abstract

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.

Keywords: Hsp27; STUbL; cystic fibrosis transmembrane conductance regulator; degradation; endoplasmic reticulum associated; proteasome; quality control; small heat shock proteins; small ubiquitin-like modifier; ubiquitin.

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Figures

Fig. 1
Fig. 1
CFTR has three SUMO consensus sites. This simplistic model showing the domain structure of CFTR indicates the locations of three predicted SUMOylation sites within the protein, one each located in NBD1, NBD2, and at the C-terminus. Whether these are the sites used in Hsp27-dependent SUMOylation requires further evaluation.
Fig. 2
Fig. 2
Putative bipolar effects of SUMOylation on CFTR. This simplified reaction scheme portrays the two opposing outcomes of CFTR SUMOylation. First, nascent CFTR is covalently modified by SUMO, mediated by Hsp27’s interaction with CFTR and the SUMO E2, Ubc9. This modification is proposed to enhance the solubility of CFTR folding intermediates during folding and domain assembly. If successful, these processes will expose the isopeptide bond(s) between CFTR and the modifier, allowing SUMO specific proteases (SENPs) to reverse the modification and yielding native, folded CFTR, ready for export to the plasma membrane. Alternatively, if SUMO remains bound to F508del CFTR, or to some fraction of misfolded WT protein, the STUbL, RNF4, recognizes the poly-SUMOylated ion channel and initiates poly-ubiquitylation, either on different lysine residues or as modifications of the SUMO poly-chain, leading to CFTR degradation by the 26S proteasome.
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