Hepatocyte OTUD1 deubiquitinates and activates ERK1/2 to promote acetaminophen-induced liver injury

Acetaminophen (APAP)-induced liver injury is one of the most common causes of liver failure. However, the critical role of deubiquitinating enzymes (DUBs) in APAP-induced hepatotoxicity remains unknown. This study elucidated for the first time the molecular mechanisms by which OUT deubiquitinase-1 (OTUD1) regulates APAP-hepatoxicity. We profiled altered expression of DUBs in liver tissues from mice challenged with APAP and identified elevated OTUD1 levels in hepatocytes. Otud1 deficiency prevented the APAP-induced hepatotoxicity. Using immunoprecipitation followed by mass spectrometry, we identified extracellular signal-regulated kinase 1/2 (ERK1/2) as the OTUD1 co-interacting protein. OTUD1 interacted with ERK1/2 and increased APAP-mediated upregulation of p-ERK1/2, which contributed to oxidative stress, inflammation, and cell death in hepatocytes. Our mechanistic studies further showed that OTUD1 deubiquitinated ERK1/2 in a K63-linked manner, leading to increased ERK1/2 phosphorylation and activity. ERK1/2 inhibition by its inhibitor SCH772984 HCl prevented the effect of OTUD1 on APAP-induced liver pathological changes in mice. In conclusion, hepatic OTUD1 is a novel APAP-response protein. The new molecular mechanism of APAP-induced hepatocyte injury involves OTUD1-mediated deubiquitination of ERK1/2, leading to enhanced ERK1/2 activity. Therefore, diminishing OTUD1 expression and function may serve as a potential therapeutic target to lessen the adverse response to APAP.