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Mol Cell. 2019 Sep 5;75(5):1058-1072.e9. doi: 10.1016/j.molcel.2019.06.028. Epub 2019 Jul 30.

The N-Degron Pathway Mediates ER-phagy.

Author information

1
Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea.
2
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.
3
World Class Institute, Anticancer Agents Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon 28116, Republic of Korea.
4
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.
5
Department of Biological Sciences, Sungkyunkwan University, Suwon 440-746, Republic of Korea. Electronic address: choicy@skku.edu.
6
Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea. Electronic address: hglee@kribb.re.kr.
7
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.
8
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.

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.

KEYWORDS:

ER homeostasis; ER protein quality control; ER stress response; ER-phagy; N-degron pathway; N-terminal arginylation; TRIM13; endoplasmic reticulum; p62; ubiquitination; α1-antitrypsin deficiency

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