Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2020.089
Endoplasmic Reticulum Stress-Mediated p62 Downregulation Inhibits Apoptosis via c-Jun Upregulation
Wenjun Yu, Busong Wang, Liang Zhou* and Guoqiang Xu*
Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu 215123, China
*E-mail: liangzhou@suda.edu.cn (Zhou L), gux2002@suda.edu.cn (Xu G)
Tel: +86-512-65882370 (Zhou L), +86-512-65882723 (Xu G)
Fax: +86-512-65882370 (Zhou L), +86-512-65882370 (Xu G)
Received: May 20, 2020; Revised: August 3, 2020; Accepted: August 28, 2020; Published online: October 13, 2020.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Cereblon (CRBN), a substrate receptor of cullin 4-RING E3 ligase (CRL4) regulates the ubiquitination and degradation of c-Jun, mediating the lipopolysaccharide-induced cellular response. However, the upstream signaling pathway that regulates this process is unknown. In this study, we describe how endoplasmic reticulum (ER) stress reversely regulates sequestosome-1 (p62)and c-Jun protein levels. Furthermore, our study reveals that expression of p62 attenuates c-Jun protein levels through the ubiquitinproteasome system. Conversely, siRNA knockdown of p62 elevates c-Jun protein levels. Immunoprecipitation and immunoblotting experiments demonstrate that p62 interacts with c-Jun and CRBN to form a ternary protein complex. Moreover, we find that CRBN knockdown completely abolishes the inhibitory effect of p62 on c-Jun. Using brefeldin A as an inducer of ER stress, we demonstrate that the p62/c-Jun axis participates in the regulation of ER stress-induced apoptosis, and that CRBN is required for this regulation. In summary, we have identified an upstream signaling pathway, which regulates p62-mediated c-Jun degradation. Our findings elucidate the underlying molecular mechanism by which p62/c-Jun axis regulates the ER stress-induced apoptosis, and provide a new molecular connection between ER stress and apoptosis.
Keywords: p62, c-Jun, CRBN, Endoplasmic reticulum stress, Apoptosis, Ubiquitination


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