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제120회 대한화학회 학술발표회, 총회 및 기기전시회 안내 The Arg/N-end rule pathway as positive regulator of autophagic flux & proteotoxic protein degradation

2017년 9월 6일 17시 38분 40초
BIO.P-291 이곳을 클릭하시면 발표코드에 대한 설명을 보실 수 있습니다.
10월 19일 (목요일) 11:00~12:30
Life Chemistry
저자 및
JEEYOUNG LEE, Won Hoon Choi, Min Jae Lee*
College of Medicine, Biochemistry, Seoul National University, Korea
The N-terminal amino acid of a protein is an essential determinant of ubiquitination and subsequent proteasomal degradation in the N-end rule pathway. We show here that blocking the arginylation branch of the pathway (Arg/N-end rule pathway) significantly impaired the fusion of autophagosomes with lysosomes by using para-chloroamphetamine (PCA) as a specific inhibitor of the Arg/N-end rule pathway. Under ER stress, the N-terminal arginylation of the ER heat shock protein HSPA5 (HSPA5/GRP78/BiP) that originally targets cargo proteins is moved out by ATE1-encoded Arg-tRNA-protein transferases in the cytosol, along with p62, to the autophagosome. At the late step of autophagy, proteasomal degradation of N-terminally arginylated HSPA5 (Arg-HSPA5) could role as a critical checkpoint for the proper progression of autophagic flux in the cells. Cells continuously treated with PCA exhibited increased levels and aggregation of autophagic markers such as LC3, p62, and proteotoxic proteins like tau and huntingtin. Treatment the Arg/N-end rule inhibitor in cells enhanced proteotoxic stress-induced cytotoxicity. Quantitative mass spectrometry with stable isotope labeling by amino acids in cell culture (SILAC) revealed that PCA significantly makes some changes in various biological pathways such as primarily cellular responses to stress, autophagic responses. Thus, the Arg/N-end rule pathway may actively protect cells from the negative influence of accumulated toxic proteins under various stress conditions. The Arg/N-end rule pathway has the first regulatory function in autophagy for substrate selection and the UPS-mediated degradation of Arg-HSPA5 helps the fusion of autolysosomes. Therefore, the Arg/N-end rule pathway may play a significant role of positively regulating autophagic flux under a number of stress conditions for protecting cells from harmful influences of proteotoxic protein accumulation.