Open AccessEndoplasmic Reticulum Stress-Mediated p62 Downregulation Inhibits Apoptosis via c-Jun Upregulation
Author(s) -
Wen-Jun Yu,
Busong Wang,
Liang Zhou,
Guoqiang Xu
Publication year - 2021
Publication title -
biomolecules and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.977
H-Index - 36
eISSN - 2005-4483
pISSN - 1976-9148
DOI - 10.4062/biomolther.2020.089
Subject(s) - downregulation and upregulation , endoplasmic reticulum , apoptosis , unfolded protein response , microbiology and biotechnology , chemistry , biology , gene , biochemistry
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 ubiquitin-proteasome system. Conversely, si RNA 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.