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論文
- タイトル
- タイトル（英）
- Intrinsic signaling pathways modulate targeted protein degradation.
- 参照URL
- https://researchmap.jp/myportal_saeki-ys/published_papers/46984952
- 著者
- 著者（英）
- Yuki Mori,Yoshino Akizuki,Rikuto Honda,Miyu Takao,Ayaka Tsuchimoto,Sota Hashimoto,Hiroaki Iio,Masakazu Kato,Ai Kaiho-Soma,Yasushi Saeki,Jun Hamazaki,Shigeo Murata,Toshikazu Ushijima,Naoko Hattori,Fumiaki Ohtake
- 担当区分
- 概要
- 概要（英）
- Targeted protein degradation is a groundbreaking modality in drug discovery; however, the regulatory mechanisms are still not fully understood. Here, we identify cellular signaling pathways that modulate the targeted degradation of the anticancer target BRD4 and related neosubstrates BRD2/3 and CDK9 induced by CRL2VHL- or CRL4CRBN -based PROTACs. The chemicals identified as degradation enhancers include inhibitors of cellular signaling pathways such as poly-ADP ribosylation (PARG inhibitor PDD00017273), unfolded protein response (PERK inhibitor GSK2606414), and protein stabilization (HSP90 inhibitor luminespib). Mechanistically, PARG inhibition promotes TRIP12-mediated K29/K48-linked branched ubiquitylation of BRD4 by facilitating chromatin dissociation of BRD4 and formation of the BRD4-PROTAC-CRL2VHL ternary complex; by contrast, HSP90 inhibition promotes BRD4 degradation after the ubiquitylation step. Consequently, these signal inhibitors sensitize cells to the PROTAC-induced apoptosis. These results suggest that various cell-intrinsic signaling pathways spontaneously counteract chemically induced target degradation at multiple steps, which could be liberated by specific inhibitors.
- 出版者・発行元
- 出版者・発行元（英）
- 誌名
- 誌名（英）
- Nature communications
- 巻
- 15
- 号
- 1
- 開始ページ
- 5379
- 終了ページ
- 5379
- 出版年月
- 2024年7月2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/s41467-024-49519-z
- 共同研究・競争的資金等の研究課題
研究者
佐伯 泰
(サエキ ヤスシ)