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論文
- タイトル
- タイトル（英）
- cIAP1-based degraders induce degradation via branched ubiquitin architectures.
- 参照URL
- https://researchmap.jp/myportal_saeki-ys/published_papers/40900570
- 著者
- 著者（英）
- Yoshino Akizuki,Mai Morita,Yuki Mori,Ai Kaiho-Soma,Shivani Dixit,Akinori Endo,Marie Shimogawa,Gosuke Hayashi,Mikihiko Naito,Akimitsu Okamoto,Keiji Tanaka,Yasushi Saeki,Fumiaki Ohtake
- 担当区分
- 概要
- 概要（英）
- Targeted protein degradation through chemical hijacking of E3 ubiquitin ligases is an emerging concept in precision medicine. The ubiquitin code is a critical determinant of the fate of substrates. Although two E3s, CRL2VHL and CRL4CRBN, frequently assemble with proteolysis-targeting chimeras (PROTACs) to attach lysine-48 (K48)-linked ubiquitin chains, the diversity of the ubiquitin code used for chemically induced degradation is largely unknown. Here we show that the efficacy of cIAP1-targeting degraders depends on the K63-specific E2 enzyme UBE2N. UBE2N promotes degradation of cIAP1 induced by cIAP1 ligands and subsequent cancer cell apoptosis. Mechanistically, UBE2N-catalyzed K63-linked ubiquitin chains facilitate assembly of highly complex K48/K63 and K11/K48 branched ubiquitin chains, thereby recruiting p97/VCP, UCH37 and the proteasome. Degradation of neo-substrates directed by cIAP1-recruiting PROTACs also depends on UBE2N. These results reveal an unexpected role for K63-linked ubiquitin chains and UBE2N in degrader-induced proteasomal degradation and demonstrate the diversity of the ubiquitin code used for chemical hijacking.
- 出版者・発行元
- 出版者・発行元（英）
- 誌名
- 誌名（英）
- Nature chemical biology
- 巻
- 号
- 開始ページ
- 終了ページ
- 出版年月
- 2022年10月31日
- 査読の有無
- 招待の有無
- 掲載種別
- 研究論文（学術雑誌）
- ISSN
- DOI URL
- https://doi.org/10.1038/s41589-022-01178-1
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