서울대학교 의과대학

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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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논문정보   
- 형식: Research article
- 게재일: 2019년 07월 (BRIC 등록일 2019-08-02)
- 연구진: 국내(교신)+국외 연구진태극기
- 분야: Cell_Biology, Biochemistry, Molecular_Biology
댓글 (1)
doinfine39  |  2019.08.17 09:16     
창훈아 제목부터 정말 멋진 논문이다! 축하해~!^^
웨비나 참석자 모집중...
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