Modulation of SQSTM1/p62 activity by N-terminal arginylation of the endoplasmic reticulum chaperone HSPA5/GRP78/BiP

Autophagy
Hyunjoo Cha-MolstadYong Tae Kwon

Abstract

The N-end rule pathway is a proteolytic system, in which single N-terminal residues act as a determinant of a class of degrons, called N-degrons. In the ubiquitin (Ub)-proteasome system, specific recognition components, called N-recognins, recognize N-degrons and accelerate polyubiquitination and proteasomal degradation of the substrates. In this study, we show that the pathway regulates the activity of the macroautophagic receptor SQSTM1/p62 (sequestosome 1) through N-terminal arginylation (Nt-arginylation) of endoplasmic reticulum (ER)-residing molecular chaperones, including HSPA5/GRP78/BiP, CALR (calreticulin), and PDI (protein disulfide isomerase). The arginylation is co-induced with macroautophagy (hereafter autophagy) as part of innate immunity to cytosolic DNA and when misfolded proteins accumulate under proteasomal inhibition. Following cytosolic relocalization and arginylation, Nt-arginylated HSPA5 (R-HSPA5) is targeted to autophagosomes and degraded by lysosomal hydrolases through the interaction of its N-terminal Arg (Nt-Arg) with ZZ domain of SQSTM1. Upon binding to Nt-Arg, SQSTM1 undergoes a conformational change, which promotes SQSTM1 self-polymerization and interaction with LC3, leading to SQSTM1 targeting to au...Continue Reading

Citations

Mar 25, 2019·Molecular Neurobiology·Cristian Gerónimo-Olvera, Lourdes Massieu
Apr 21, 2017·Frontiers in Neuroscience·Caty Casas
Aug 28, 2021·Biomedicines·Tatiana Leiva-RodríguezCaty Casas

❮ Previous
Next ❯

Methods Mentioned

BETA
ubiquitination

Related Concepts

Related Feeds

Autophagosome

An autophagosome is the formation of double-membrane vesicles that involve numerous proteins and cytoplasmic components. These double-membrane vesicles are then terminated at the lysosome where they are degraded. Discover the latest research on autophagosomes here.

Autophagosome

An autophagosome is the formation of double-membrane vesicles that involve numerous proteins and cytoplasmic components. These double-membrane vesicles are then terminated at the lysosome where they are degraded. Discover the latest research on autophagosomes here.

Autophagy & Aging: Inhibitors

The feed focuses on the role of nuclear export inhibitors and their effect on autophagy and the aging process.

Autophagy & Model Organisms

Autophagy is a cellular process that allows degradation by the lysosome of cytoplasmic components such as proteins or organelles. Here is the latest research on autophagy & model organisms

Related Papers

Nature Structural & Molecular Biology
Shashikanth M Sriram, Yong Tae Kwon
Annual Review of Biochemistry
Takafumi TasakiYong Tae Kwon
Proceedings of the National Academy of Sciences of the United States of America
Takafumi TasakiYong Tae Kwon
© 2022 Meta ULC. All rights reserved