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Title 

The arginylation branch of the N-end rule pathway positively regulates cellular autophagic flux and clearance of proteotoxic proteins

Authors 

Y JiangJ LeeJ H LeeJ W LeeJ H KimW H ChoiY D YooHyunjoo ChaBo Yeon KimY T KwonS A NohK P KimM J Lee

Publisher 

Landes Bioscience

Issue Date 

2016

Citation 

Autophagy, vol. 12, no. 11, pp. 2197-2212

Keywords 

ATE1autophagyHSPA5N-end rule pathwayneurodegenerative diseasepara-chloroamphetamineubiquitin-proteasome system

Abstract 

The N-terminal amino acid of a protein is an essential determinant of ubiquitination and subsequent proteasomal degradation in the N-end rule pathway. Using para-chloroamphetamine (PCA), a specific inhibitor of the arginylation branch of the pathway (Arg/N-end rule pathway), we identified that blocking the Arg/N-end rule pathway significantly impaired the fusion of autophagosomes with lysosomes. Under ER stress, ATE1-encoded Arg-tRNA-protein transferases carry out the N-terminal arginylation of the ER heat shock protein HSPA5 that initially targets cargo proteins, along with SQSTM1, to the autophagosome. At the late stage of autophagy, however, proteasomal degradation of arginylated HSPA5 might function as a critical checkpoint for the proper progression of autophagic flux in the cells. Consistently, the inhibition of the Arg/N-end rule pathway with PCA significantly elevated levels of MAPT and huntingtin aggregates, accompanied by increased numbers of LC3 and SQSTM1 puncta. Cells treated with the Arg/N-end rule inhibitor became more sensitized to proteotoxic stress-induced cytotoxicity. SILAC-based quantitative proteomics also revealed that PCA significantly alters various biological pathways, including cellular responses to stress, nutrient, and DNA damage, which are also closely involved in modulation of autophagic responses. Thus, our results indicate that the Arg/N-end rule pathway may function to actively protect cells from detrimental effects of cellular stresses, including proteotoxic protein accumulation, by positively regulating autophagic flux.

ISSN 

1554-8627

Link 

http://dx.doi.org/10.1080/15548627.2016.1222991

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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