The N-degron pathway mediates ER-phagy

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The N-degron pathway mediates ER-phagy
C H Ji; H Y Kim; A J Heo; S H Lee; M J Lee; S B Kim; G Srinivasrao; S R Mun; Hyunjoo Cha; C Y Choi; Hee Gu LeeBo Yeon Kim; Y T Kwon
Bibliographic Citation
Molecular Cell, vol. 75, no. 5, pp. 1058-1072
Publication Year
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.
TRIM13α1-antitrypsin deficiencyER-phagyendoplasmic reticulumER homeostasisER protein quality controlER stress responseN-degron pathwayubiquitinationN-terminal arginylationp62
Elsevier-Cell Press
Appears in Collections:
Ochang Branch Institute > Nucleic Acid Therapeutics Research Center > 1. Journal Articles
Division of Biomedical Research > Immunotherapy Research Center > 1. Journal Articles
Ochang Branch Institute > Chemical Biology Research Center > 1. Journal Articles
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