PRDX1通过在结直肠癌中与Cullin-3作为分子伴侣结合来抑制铁蛋白
PRDX1 inhibits ferroptosis by binding to Cullin-3 as a molecular chaperone in colorectal cancer
影响因子:10.00000
分区:生物学1区 Top / 生化与分子生物学2区
发表日期:2024
作者:
Yujia Song, Xiaohui Wang, Yuqi Sun, Nianhua Yu, Yajie Tian, Jinli Han, Xianjun Qu, Xinfeng Yu
摘要
过氧蛋白1（PRDX1）是一种有效的抗氧化剂蛋白，可显示独特的分子伴侣活性。但是，PRDX1在结直肠癌（CRC）中的过表达的作用是难以捉摸的。在此，我们发现PRDX1敲除小鼠中与AOM/DSS诱导的结肠炎相关的CRC的数量明显低于野生型小鼠的数量，这与NRF2和GPX4的下调同时。从机械上讲，RNA测序结果表明，PRDX1的敲低导致NRF2的显着降低，这进一步触发了ROS诱导的线粒体功能障碍和脂质过氧化诱导的CRC细胞中的脂肪诱导。值得注意的是，PRDX1抑制NRF2降解并促进NRF2核转运，从而触发GPX4的转录。免疫沉淀 - 质谱法（IP-MS）和共免疫沉淀（CO-IP）测定法显示，PRDX1可以通过与CUL3结合以抑制NRF2泛素化来充当分子伴侣。重要的是，Conoidin A增强了PRDX1与CUL3的结合，但被PRDX1 CYS83SER突变体废除。 PRDX1敲低对CRC的抑制作用可能会因体内NRF2激活或Ferrostatin-1给药而减弱。总的来说，这些结果为PRDX1的分子伴侣活性提供了一种新的见解，这是通过抑制CUL3介导的NRF2降解来促进CRC进展的，这表明PRDX1 CYS83是抑制CRC的潜在药物靶标。
Abstract
Peroxiredoxin 1 (PRDX1) is a potent antioxidant protein that displays a unique molecular chaperone activity. However, the role of overexpression of PRDX1 in colorectal cancer (CRC) was elusive. Herein, we found that the number of AOM/DSS-induced colitis-associated CRC in PRDX1 knockout mice was significantly lower than that in wild-type mice, concomitant with the downregulation of NRF2 and GPX4. Mechanistically, RNA sequencing results indicated that knockdown of PRDX1 resulted in a significant reduction of NRF2, which further triggered ROS-induced mitochondrial dysfunction and lipid peroxidation-induced ferroptosis in CRC cells. Notably, PRDX1 inhibited NRF2 degradation and promoted NRF2 nuclear translocation, thereby triggering the transcription of GPX4. Immunoprecipitation-mass spectrometry (IP-MS) and Co-immunoprecipitation (Co-IP) assays revealed that PRDX1 could act as a molecular chaperone by binding to CUL3 to inhibit NRF2 ubiquitination. Importantly, the binding of PRDX1 to CUL3 was enhanced by conoidin A but abolished by the PRDX1 Cys83Ser mutant. The inhibitory effects of PRDX1 knockdown on CRC could be attenuated by NRF2 activation or ferrostatin-1 administration in vivo. Collectively, these results provide a novel insight into the molecular chaperone activity of PRDX1 in promoting CRC progression through suppression of CUL3-mediated NRF2 degradation, suggesting PRDX1 Cys83 is a potential drug target in inhibiting CRC.