論文 - 詳細
| RRC ID | 59768 |
|---|---|
| 著者 | Takahashi D, Moriyama J, Nakamura T, Miki E, Takahashi E, Sato A, Akaike T, Itto-Nakama K, Arimoto H. |
| タイトル | AUTACs: Cargo-Specific Degraders Using Selective Autophagy. |
| ジャーナル | Mol Cell |
| Abstract |
Protein silencing represents an essential tool in biomedical research. Targeted protein degradation (TPD) strategies exemplified by PROTACs are rapidly emerging as modalities in drug discovery. However, the scope of current TPD techniques is limited because many intracellular materials are not substrates of proteasomal clearance. Here, we described a novel targeted-clearance strategy (autophagy-targeting chimera [AUTAC]) that contains a degradation tag (guanine derivatives) and a warhead to provide target specificity. As expected from the substrate scope of autophagy, AUTAC degraded fragmented mitochondria as well as proteins. Mitochondria-targeted AUTAC accelerated both the removal of dysfunctional fragmented mitochondria and the biogenesis of functionally normal mitochondria in patient-derived fibroblast cells. Cytoprotective effects against acute mitochondrial injuries were also seen. Canonical autophagy is viewed as a nonselective bulk decomposition system, and none of the available autophagy-inducing agents exhibit useful cargo selectivity. With its target specificity, AUTAC provides a new modality for research on autophagy-based drugs. |
| 巻・号 | 76(5) |
| ページ | 797-810.e10 |
| 公開日 | 2019-12-5 |
| DOI | 10.1016/j.molcel.2019.09.009 |
| PII | S1097-2765(19)30694-X |
| PMID | 31606272 |
| MeSH | Autophagy / physiology* Autophagy-Related Proteins / metabolism Cell Line Guanine / chemistry* Guanine / physiology Humans Mitochondria / metabolism Mitophagy / physiology Protein Engineering / methods Protein Kinases / metabolism Protein Stability Proteolysis / drug effects* |
| IF | 14.548 |
| 引用数 | 17 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 192 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 9.5 |
| リソース情報 | |
| ヒト・動物細胞 | HeLa(RCB0007) A549(RCB0098) RAW 264(RCB0535) Hep G2(RCB1886) C6(RCB2854) Atg5^(-/-)MEF(RCB2711) |