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Regulation of reticulophagy by the N-degron pathway.

Authors :
Ji, Chang Hoon
Kim, Hee Yeon
Heo, Ah Jung
Lee, Min Ju
Park, Daniel Youngjae
Kim, Dong Hyun
Kim, Bo Yeon
Kwon, Yong Tae
Source :
Autophagy; Feb2020, Vol. 16 Issue 2, p373-375, 3p
Publication Year :
2020

Abstract

Cellular homeostasis requires selective autophagic degradation of damaged or defective organelles, including the endoplasmic reticulum (ER). Previous studies have shown that specific ER transmembrane receptors recruit LC3 on autophagic membranes by using LC3-interacting domains. In this study, we showed that the N-degron pathway mediates ubiquitin (Ub)-dependent reticulophagy. During this 2-step process, the ER transmembrane E3 ligase TRIM13 undergoes auto-ubiquitination via lysine 63 (K63) linkage chains and acts as a ligand for the autophagic receptor SQSTM1/p62 (sequestosome 1). In parallel, ER-residing molecular chaperones, such as HSPA5/GRP78/BiP, are relocated to the cytosol and conjugated with the amino acid L-arginine (Arg) at the N-termini by ATE1 (arginyltransferase 1). The resulting N-terminal Arg (Nt-Arg) binds the ZZ domain of SQSTM1, inducing oligomerization of SQSTM1-TRIM13 complexes and facilitating recruitment of LC3 on phagophores to the sites of reticulophagy. We developed small molecule ligands to the SQSTM1 ZZ domain and demonstrate that these chemical mimics of Nt-Arg facilitate reticulophagy and autophagic protein quality control of misfolded aggregates in the ER. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
15548627
Volume :
16
Issue :
2
Database :
Complementary Index
Journal :
Autophagy
Publication Type :
Academic Journal
Accession number :
141313074
Full Text :
https://doi.org/10.1080/15548627.2019.1695402