Trim21调节内质网相关降解并通过抑制VCP/Npl4/UFD1复合物装配增强癌细胞对ER应激诱导的凋亡
Trim21 modulates endoplasmic reticulum-associated degradation and sensitizes cancer cells to ER stress-induced apoptosis by inhibiting VCP/Npl4/UFD1 assembly
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影响因子:4.2
分区:生物学2区 / 生物物理2区 生化与分子生物学3区
发表日期:2025 Jan
作者:
Chao Yuan, Yanli Liao, WenXia Si, Mi Huang, Duanzhuo Li, Fuqing Wang, Yi Quan, Xin Yu, Shengjie Liao
DOI:
10.1016/j.bbadis.2024.167533
摘要
内质网相关降解（ERAD）是一个关键的质量与数量控制系统，通过细胞质泛素-蛋白酶体系统（UPS）清除内质网（ER）内错误折叠或未组装的蛋白质，关乎细胞命运的决定。当错误折叠的蛋白堆积在内质网腔内时，会引发内质网应激，可能通过促凋亡的未折叠蛋白反应（UPR）导致细胞死亡。UFD1与VCP-Npl4结合，被认为是调控ERAD中蛋白稳态的关键因子。然而，调控VCP复合物组装的因素尚不明确。研究表明，E3泛素连接酶Trim21通过与UFD1的相互作用，促使UFD1的K27连接泛素化，抑制其加入VCP复合物，从而抑制ERAD底物的降解，激活促凋亡的未折叠蛋白反应。在ER诱导剂Tunicamycin作用下，Trim21的过表达增强了ER应激反应并促进细胞凋亡。值得注意的是，Trim21表达升高与多种肿瘤类型的总体生存期改善相关。总体而言，研究结果强调了Trim21在调控ERAD进程及癌细胞命运中的关键作用，通过调节VCP/Npl4/UFD1复合物的组装实现。
Abstract
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.