Endoplasmic Reticulum Stress-Mediated p62 Downregulation Inhibits Apoptosis via c-Jun Upregulation.
Endoplasmic Reticulum Stress-Mediated p62 Downregulation Inhibits Apoptosis via c-Jun Upregulation.
复制标题
内质网应激介导的 p62 下调通过 c-Jun 上调抑制细胞凋亡
DOI：
10.4062/biomolther.2020.089
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发表时间：
2021-03-01
影响因子：
3.7
通讯作者：
Xu G
中科院分区：
文献类型：
--
作者：
Yu W;Wang B;Zhou L;Xu G
Cereblon（CRBN）是cullin 4-RING E3连接酶（CRL 4）的底物受体，调节c-Jun的泛素化和降解，介导脂多糖诱导的细胞反应。然而，调控这一过程的上游信号通路是未知的。在这项研究中，我们描述了内质网（ER）的应激反应如何调节螯合体-1（p62）和c-Jun蛋白水平。此外，我们的研究表明，p62的表达通过泛素-蛋白酶体系统减弱c-Jun蛋白水平。相反，p62的siRNA敲低提高了c-Jun蛋白水平。免疫沉淀和免疫印迹实验表明，p62与c-Jun和CRBN相互作用，形成三元蛋白复合物。此外，我们发现，CRBN敲除完全废除p62对c-Jun的抑制作用。使用布雷菲德菌素A作为ER应激诱导剂，我们证明，p62/c-Jun轴参与ER应激诱导的细胞凋亡的调节，CRBN是需要这种调节。总之，我们已经确定了一个上游信号通路，调节p62介导的c-Jun降解。我们的研究结果阐明了p62/c-Jun轴调控内质网应激诱导的细胞凋亡的分子机制，为内质网应激与细胞凋亡之间的关系提供了新的分子联系。
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, 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.