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.
Mesh Terms:
Aged, Aged, 80 and over, Aminopyridines, Animals, B7-H1 Antigen, Carcinogenesis, Case-Control Studies, Colorectal Neoplasms, Endopeptidases, Female, Humans, Immune Checkpoint Inhibitors, Lipogenesis, Male, Mice, Inbred C57BL, Middle Aged, Mitogen-Activated Protein Kinase 1, Phosphorylation, Pyrroles, Reactive Oxygen Species, Ubiquitination, Vesicular Transport Proteins
Aged, Aged, 80 and over, Aminopyridines, Animals, B7-H1 Antigen, Carcinogenesis, Case-Control Studies, Colorectal Neoplasms, Endopeptidases, Female, Humans, Immune Checkpoint Inhibitors, Lipogenesis, Male, Mice, Inbred C57BL, Middle Aged, Mitogen-Activated Protein Kinase 1, Phosphorylation, Pyrroles, Reactive Oxygen Species, Ubiquitination, Vesicular Transport Proteins
Cell Rep
Date: Dec. 28, 2020
PubMed ID: 34965422
View in: Pubmed Google Scholar
Download Curated Data For This Publication
235265
Switch View:
- Interactions 10