Opposite regulation of F508del-CFTR biogenesis by four poly-lysine ubiquitin chains In vitro

• Published in: Biochimica et biophysica acta. Proteins and proteomics 2022-06, Vol.1870 (6), p.140792-140792, Article 140792
• Main Authors: Wu, Qingtian, Henri, Yonta Tiakouang, Yao, Ruixue, Yu, Lianpeng, Zhang, Bo, Wang, Zixin, Ma, Xuemei, Zhao, Gang, Hou, Xia
• Format: Article
• Language: English
• Subjects: Cystic Fibrosis - genetics; Cystic Fibrosis - metabolism; Cystic Fibrosis - pathology; Cystic Fibrosis Transmembrane Conductance Regulator - chemistry; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; F508del-CFTR; Humans; Lysine; Lysine linked polyubiquitin chain; Proteasomal degradation; Proteasome Endopeptidase Complex - metabolism; Ubiquitin
• ISSN: 1570-9639; 1878-1454
• DOI: 10.1016/j.bbapap.2022.140792

As a misfolding protein, almost all of F508del-CFTR is degraded by the ubiquitin–proteasome system before its maturation, which results in no membrane expression of cystic fibrosis transmembrane conductance regulator (CFTR) and therefore, no chloride secretion across epithelial cells of cystic fibrosis (CF) patients. The conjugation of ubiquitin (Ub) chains to protein substrates is necessary for the proteasomal degradation of F508del-CFTR. Ubiquitin contains seven lysine (K) residues, all of which can be conjugated to one another, forming poly-ubiquitin chains on substrates, either by mixing together, or by only one type of lysine providing sorting signals for different pathways. Here, we report that four lysine-linked poly-Ub chains (LLPUCs) were involved in F508del-CFTR biogenesis: LLPUCs linked by K11 or K48 facilitated F508del-CFTR degradation, whereas the other two linked by K63 and K33 protected F508del-CFTR from degradation. LLPUC K11 is more potent for F508del-CFTR degradation than K48. F508del-CFTR utilizes four specific lysine-linked poly-Ub chains during its biogenesis for opposite destiny through different identification by proteasomal shuttle protein or receptors. These findings provide new insights into the CF pathogenesis and are expected to facilitate the development of therapies for this devastating disease. •LLPUCs of K11on Ub facilitated F508del-CFTR degradation more than orLLPUCs of K48.•LLPUCs of K63 and K33 on Ub protected F508del-CFTR from degradation.•E3 ligase CHIP and RNF5 catalyzed LLPUCs K48 formation and RNF5 also catalyzed LLPUC K11 formation on F508del-CFTR.•Those LLPUCs provide F508del-CFTR with different affinities to the proteasomal shuttle protein Rad23a and the proteasomal receptors Adrm1 and S5a.