内质网相关降解（ERAD）是一个关键的质量和数量控制系统，它通过细胞质泛素蛋白酶体系统（UPS）从内质网（ER）中去除错误折叠或未组装的蛋白质，这对于细胞命运的决定至关重要。当错误折叠的蛋白质在内质网腔内积累时，就会产生内质网应激，并可能通过促凋亡未折叠蛋白反应（UPR）导致细胞死亡。 UFD1 与 VCP-Npl4 相关，被认为是 ERAD 中蛋白质稳态的关键调节因子。然而，控制VCP复合体组装的因素仍不清楚。该研究阐明了 Trim21（一种 E3 泛素连接酶）的功能，通过与 UFD1 相互作用，促进 UFD1 的 K27 连接泛素化并抑制其掺入 VCP 复合物。这导致癌细胞中 ERAD 底物降解的抑制和促凋亡未折叠蛋白反应的激活。此外，Trim21 过度表达可增强 ER 应激反应，并在暴露于 ER 诱导剂衣霉素后促进细胞凋亡。值得注意的是，Trim21 表达升高与各种肿瘤类型的总体生存率提高相关。总体而言，这些研究结果强调了 Trim21 通过调节 VCP/Npl4/UFD1 复合物组装来调节癌细胞中 ERAD 进展和细胞命运决定的关键作用。版权所有 © 2024。由 Elsevier B.V. 出版。

Endoplasmic reticulum-associated degradation (ERAD) serves as a crucial quality and quantity control system that removes misfolded or unassembled proteins from the Endoplasmic Reticulum (ER) through the cytoplasmic ubiquitin-proteasome system (UPS), which is critical for cell fate decision. ER stress arises when misfolded proteins accumulated within the ER lumen, potentially leading to cell death via proapoptotic unfolded protein response (UPR). UFD1 in associated with VCP-Npl4, is recognized as a key regulator of protein homeostasis in ERAD. However, the factors that control VCP complex assembly remain unclear. The study elucidates the function of Trim21, an E3 ubiquitin ligase, through its interaction with UFD1, facilitating K27-linkage ubiquitination of UFD1 and inhibiting its incorporation into the VCP complex. This results in the suppression of ERAD substrates degradation and the activation of a proapoptotic unfolded protein response in cancer cells. Additionally, Trim21 over-expression enhances ER stress response and promotes apoptosis upon expose to the ER inducer Tunicamycin. Notably, elevated Trim21 expression correlates with improved overall survival in various tumor types. Overall, the findings highlight the critical role of Trim21 in regulating ERAD progression and cell fate determination in cancer cells through modulation of VCP/Npl4/UFD1 complex assembly.Copyright © 2024. Published by Elsevier B.V.