The N-Degron Pathway Mediates ER-phagy.
| Autor: | Ji CH; Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea., Kim HY; Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea; AUTOTAC, Changkkyunggung-ro 254, Jongno-gu, Seoul 110-799, Republic of Korea., Heo AJ; Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea., Lee SH; Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea., Lee MJ; Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea., Kim SB; Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea., Srinivasrao G; Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea; AUTOTAC, Changkkyunggung-ro 254, Jongno-gu, Seoul 110-799, Republic of Korea., Mun SR; Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea., Cha-Molstad H; World Class Institute, Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon 28116, Republic of Korea., Ciechanover A; Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea; Technion Integrated Cancer Center, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3109601, Israel., Choi CY; Department of Biological Sciences, Sungkyunkwan University, Suwon 440-746, Republic of Korea. Electronic address: choicy@skku.edu., Lee HG; Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea. Electronic address: hglee@kribb.re.kr., Kim BY; World Class Institute, Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon 28116, Republic of Korea. Electronic address: bykim@kribb.re.kr., Kwon YT; Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea; Protech, Yongeon 103 Daehangno, Jongno-gu, Seoul 110-799, Republic of Korea; Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea. Electronic address: yok5@snu.ac.kr. |
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| Jazyk: | angličtina |
| Zdroj: | Molecular cell [Mol Cell] 2019 Sep 05; Vol. 75 (5), pp. 1058-1072.e9. Date of Electronic Publication: 2019 Jul 30. |
| DOI: | 10.1016/j.molcel.2019.06.028 |
| Abstrakt: | 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. (Copyright © 2019 Elsevier Inc. All rights reserved.) |
| Databáze: | MEDLINE |
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