한빛사 논문
Chang Hoon Ji1,9, Hee Yeon Kim1,2,9, Ah Jung Heo1,9, Su Hyun Lee1, Min Ju Lee1, Su Bin Kim1, Ganipisetti Srinivasrao1,2, Su Ran Mun1, Hyunjoo Cha-Molstad3, Aaron Ciechanover1,4, Cheol Yong Choi5,*, Hee Gu Lee6,*, Bo Yeon Kim3,*, Yong Tae Kwon1,7,8,10,*
1 Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea
2 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 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
6 Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
7 Protech, Yongeon 103 Daehangno, Jongno-gu, Seoul 110-799, Republic of Korea
8 Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea
9 These authors contributed equally
10 Lead Contact
*Corresponding author
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-phagy; endoplasmic reticulum; ER homeostasis; ER protein quality control; ER stress response; N-degron pathway; ubiquitination; N-terminal arginylation; p62; TRIM13; α1-antitrypsin deficiency
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