USP19 exacerbates lipogenesis and colorectal carcinogenesis by stabilizing ME1

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. [Display omitted] •ERK2 phosphorylates ME1 T103 to promote USP19 deubiquitinating and stabilizing ME1•USP19 deficiency attenuates lipogenesis and colorectal tumorigenesis in mice•ERK2 inhibition increases NRF2 trans-activating PD-L1 via ME1-mediated ROS reduction•USP19/ME1 is dysregulated, and combined targeting of ERK2/PD-L1 is effective in CRCs Zhu et al. demonstrate that ERK2 phosphorylates ME1 T103, thereby enhancing USP19 to deubiquitinate and stabilize ME1 in CRC, thus increasing lipogenesis, NADPH production, and tumorigenesis and inhibiting ROS. ERK2 inhibition increases NRF2 and triggers PD-L1 transcription via ME1-mediated ROS reduction. Combined targeting of ERK2 and PD-L1 is effective against CRC.