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Title 

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

Authors 

Hyunjoo ChaSu Hyun LeeJung Gi KimK W SungJoonsung HwangS M ShimS GanipisettiT McGuireI Mook-JungA CiechanoverX Q XieBo Yeon KimY T Kwon

Publisher 

Landes Bioscience

Issue Date 

2018

Citation 

Autophagy

Keywords 

ATE1 R-transferaseN-end rule pathwayprotein arginylationprotein quality controlproteolysis

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

ISSN 

1554-8627

Link 

http://dx.doi.org/10.1080/15548627.2017.1415190

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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