TRIM21通过抑制VCP/NPL4/UFD1组装来调节内质网相关的降解，并使癌细胞对ER应激诱导的凋亡敏感
Trim21 modulates endoplasmic reticulum-associated degradation and sensitizes cancer cells to ER stress-induced apoptosis by inhibiting VCP/Npl4/UFD1 assembly
影响因子:4.20000
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
摘要
内质网相关降解（ERAD）是一种至关重要的质量和数量控制系统，可以通过细胞质泛素 - 泛素 - 蛋白酶体系统（UPS）去除内质网（ER）的错误折叠或未组装的蛋白质，这对于细胞命运至关重要。当累积在ER腔内的蛋白质中折叠式蛋白质时，会产生ER应激，这可能会导致细胞死亡通过促凋亡展开的蛋白质反应（UPR）。与VCP-NPL4相关的UFD1被认为是ERAD蛋白稳态的关键调节剂。但是，控制VCP复合物组件的因素尚不清楚。该研究通过与UFD1的相互作用阐明了TRIM21（E3泛素连接酶）的功能，从而促进了UFD1的K27-链接泛素化，并抑制了其掺入VCP复合物。这导致抑制ERAD底物降解以及癌细胞中促凋亡的蛋白质反应的激活。此外，TRIM21过表达增强了ER应力反应，并在暴露于ER诱导蛋白穿牙霉素后促进凋亡。值得注意的是，升高的TRIM21表达与各种肿瘤类型的总体存活率提高相关。总体而言，这些发现突出了TRIM21在通过调节VCP/NPL4/UFD1复合物组装中调节癌细胞中ERAD进展和细胞命运测定的关键作用。
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.