Medical Research Institute, Guangdong Cardiovascular Institute, Guangdong Geriatrics Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China.
Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, 400038, China.
Cell Death Dis. 2023 Apr 1;14(4):233. doi: 10.1038/s41419-023-05752-w.
Necroptosis plays a double-edged sword role in necroptotic cancer cell death and tumor immune escape. How cancer orchestrates necroptosis with immune escape and tumor progression remains largely unclear. We found that RIP3, the central activator of necroptosis, was methylated by PRMT1 methyltransferase at the amino acid of RIP3 R486 in human and the conserved amino acid R479 in mouse. The methylation of RIP3 by PRMT1 inhibited the interaction of RIP3 with RIP1 to suppress RIP1-RIP3 necrosome complex, thereby blocking RIP3 phosphorylation and necroptosis activation. Moreover, the methylation-deficiency RIP3 mutant promoted necroptosis, immune escape and colon cancer progression due to increasing tumor infiltrated myeloid-derived immune suppressor cells (MDSC), while PRMT1 reverted the immune escape of RIP3 necroptotic colon cancer. Importantly, we generated a RIP3 R486 di-methylation specific antibody (RIP3). Clinical patient samples analysis revealed that the protein levels of PRMT1 and RIP3 were positively correlated in cancer tissues and both of them predicted the longer patient survival. Our study provides insights into the molecular mechanism of PRMT1-mediated RIP3 methylation in the regulation of necroptosis and colon cancer immunity, as well as reveals PRMT1 and RIP3 as the valuable prognosis markers of colon cancer.
细胞程序性坏死在细胞坏死性死亡和肿瘤免疫逃逸中起着双刃剑的作用。癌细胞如何通过免疫逃逸和肿瘤进展来协调细胞程序性坏死仍然很大程度上不清楚。我们发现，细胞程序性坏死的核心激活剂 RIP3 在人类的 RIP3 R486 氨基酸和小鼠的保守氨基酸 R479 处被 PRMT1 甲基转移酶甲基化。PRMT1 对 RIP3 的甲基化抑制了 RIP3 与 RIP1 的相互作用，从而抑制了 RIP1-RIP3 坏死小体复合物的形成，从而阻止了 RIP3 的磷酸化和细胞程序性坏死的激活。此外，由于肿瘤浸润的髓系来源免疫抑制细胞（MDSC）增加，甲基化缺陷的 RIP3 突变体促进了细胞程序性坏死、免疫逃逸和结肠癌的进展，而 PRMT1 则使 RIP3 细胞程序性坏死的结肠癌恢复了免疫逃逸。重要的是，我们生成了一种 RIP3 R486 二甲基化特异性抗体（RIP3）。临床患者样本分析显示，PRMT1 和 RIP3 的蛋白水平在癌症组织中呈正相关，两者均预测患者的生存期更长。我们的研究为 PRMT1 介导的 RIP3 甲基化在调节细胞程序性坏死和结肠癌免疫中的分子机制提供了深入的了解，并揭示了 PRMT1 和 RIP3 是结肠癌有价值的预后标志物。
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