論文 - 詳細
| RRC ID | 57983 |
|---|---|
| 著者 | Ji CH, Kim HY, Heo AJ, Lee SH, Lee MJ, Kim SB, Srinivasrao G, Mun SR, Cha-Molstad H, Ciechanover A, Choi CY, Lee HG, Kim BY, Kwon YT. |
| タイトル | The N-Degron Pathway Mediates ER-phagy. |
| ジャーナル | Mol Cell |
| Abstract |
The endoplasmic reticulum (ER) is susceptible to wear-and-tear and proteotoxic stress, necessitating its turnover. Here, we show that the N-degron pathway mediates ER-phagy. This autophagic degradation initiates when the transmembrane E3 ligase TRIM13 (also known as RFP2) is ubiquitinated via the lysine 63 (K63) linkage. K63-ubiquitinated TRIM13 recruits p62 (also known as sequestosome-1), whose complex undergoes oligomerization. The oligomerization is induced when the ZZ domain of p62 is bound by the N-terminal arginine (Nt-Arg) of arginylated substrates. Upon activation by the Nt-Arg, oligomerized TRIM13-p62 complexes are separated along with the ER compartments and targeted to autophagosomes, leading to lysosomal degradation. When protein aggregates accumulate within the ER lumen, degradation-resistant autophagic cargoes are co-segregated by ER membranes for lysosomal degradation. We developed synthetic ligands to the p62 ZZ domain that enhance ER-phagy for ER protein quality control and alleviate ER stresses. Our results elucidate the biochemical mechanisms and pharmaceutical means that regulate ER homeostasis. |
| 巻・号 | 75(5) |
| ページ | 1058-1072.e9 |
| 公開日 | 2019-9-5 |
| DOI | 10.1016/j.molcel.2019.06.028 |
| PII | S1097-2765(19)30485-X |
| PMID | 31375263 |
| MeSH | Animals Carrier Proteins / genetics Carrier Proteins / metabolism* Endoplasmic Reticulum / genetics Endoplasmic Reticulum / metabolism* HEK293 Cells HeLa Cells Humans Mice Mice, Knockout Proteolysis* Sequestosome-1 Protein / genetics Sequestosome-1 Protein / metabolism* Ubiquitination |
| IF | 15.584 |
| 引用数 | 8 |
| 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 | 29 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | Atg5^(+/+)MEF(RCB2710) Atg5^(-/-)MEF(RCB2711) |