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Autophagy. 2018;14(2):359-361. doi: 10.1080/15548627.2017.1415190. Epub 2018 Jan 29.

Regulation of autophagic proteolysis by the N-recognin SQSTM1/p62 of the N-end rule pathway.

Author information

1
a Anticancer Agent Research Center (WCI) , Korea Research Institute of Bioscience and Biotechnology (KRIBB) , Cheongju-si , Korea.
2
b Protein Metabolism Medical Research Center and Department of Biomedical Sciences, College of Medicine , Seoul National University , Seoul , Korea.
3
c Department of Biomolecular Science, KRIBB School of Bioscience , Korea University of Science and Technology (UST) , Daejeon , South Korea.
4
d Computational Chemogenomics Screen Center, Department of Pharmaceutical Sciences, and National Center of Excellence for Drug Abuse.
5
e Department of Biochemistry and Biomedical Sciences , Seoul National University College of Medicine , Seoul , Korea.
6
f The Polak Tumor and Vascular Biology Research Center , The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology , Haifa , Israel.
7
g Ischemic/Hypoxic Disease Institute, College of Medicine , Seoul National University , Seoul, Korea.

Abstract

In macroautophagy/autophagy, cargoes are collected by specific receptors, such as SQSTM1/p62 (sequestosome 1), and delivered to phagophores for lysosomal degradation. To date, little is known about how cells modulate SQSTM1 activity and autophagosome biogenesis in response to accumulating cargoes. In this study, we show that SQSTM1 is an N-recognin whose ZZ domain binds N-terminal arginine (Nt-Arg) and other N-degrons (Nt-Lys, Nt-His, Nt-Trp, Nt-Phe, and Nt-Tyr) of the N-end rule pathway. The substrates of SQSTM1 include the endoplasmic reticulum (ER)-residing chaperone HSPA5/GRP78/BiP. Upon N-end rule interaction with the Nt-Arg of arginylated HSPA5 (R-HSPA5), SQSTM1 undergoes self-polymerization via disulfide bonds of Cys residues including Cys113, facilitating cargo collection. In parallel, Nt-Arg-bound SQSTM1 acts as an inducer of autophagosome biogenesis and autophagic flux. Through this dual regulatory mechanism, SQSTM1 plays a key role in the crosstalk between the ubiquitin (Ub)-proteasome system (UPS) and autophagy. Based on these results, we employed 3D-modeling of SQSTM1 and a virtual chemical library to develop small molecule ligands to the ZZ domain of SQSTM1. These autophagy inducers accelerated the autophagic removal of mutant HTT (huntingtin) aggregates. We suggest that SQSTM1 can be exploited as a novel drug target to modulate autophagic processes in pathophysiological conditions.

KEYWORDS:

ATE1 R-transferase; N-end rule pathway; protein arginylation; protein quality control; proteolysis

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