Lipogenesis plays a critical role in colorectal carcinogenesis, but precisely how remains unclear. Here, we show that ERK2 phosphorylates ME1 at T103, thereby inhibiting its polyubiquitination and proteasomal degradation and enhancing its interaction with USP19. USP19 antagonizes RNF1-mediated ME1 degradation by deubiquitination, which in turn promotes lipid metabolism and NADPH production and suppresses ROS. Meanwhile, ROS dramatically increases PD-L1 mRNA levels through accelerating expression of the transcription factor NRF2. Increased lipid metabolism is correlated with ERK2 activity and colorectal carcinogenesis in human patients. Therefore, the combination of ERK2 inhibitor and anti-PD-L1 antibody significantly inhibits spontaneous and chemically induced colorectal carcinogenesis. Collectively, the USP19-ME1 axis plays a vital role in colorectal carcinogenesis and may also provide a potential therapeutic target.

脂肪生成在结直肠癌发生中起关键作用，但具体如何尚不清楚。在这里，我们显示 ERK2 在 T103 磷酸化 ME1，从而抑制其多泛素化和蛋白酶体降解并增强其与 USP19 的相互作用。USP19 通过去泛素化拮抗 RNF1 介导的 ME1 降解，进而促进脂质代谢和 NADPH 产生并抑制 ROS。同时，ROS 通过加速转录因子 NRF2 的表达显着增加 PD-L1 mRNA 水平。增加的脂质代谢与人类患者的 ERK2 活性和结肠直肠癌发生相关。因此，ERK2抑制剂和抗PD-L1抗体的组合显着抑制自发和化学诱导的结肠直肠癌发生。集体，