USP8 inhibition regulates autophagy flux and controls Salmonella infection

Abstract

IntroductionUbiquitination is an important protein modification that regulates various essential cellular processes, including the functions of innate immune cells. Deubiquitinases are enzymes responsible for removing ubiquitin modification from substrates, and the regulation of deubiquitinases in macrophages during infection with Salmonella Typhimurium and Yersinia enterocolitica remains unknown.MethodsTo identify deubiquitinases regulated in human macrophages during bacterial infection, an activity-based proteomics screen was conducted. The effects of pharmacological inhibition of the identified deubiquitinase, USP8, were examined, including its impact on bacterial survival within macrophages and its role in autophagy regulation during Salmonella infection.ResultsSeveral deubiquiitnases were differentially regulated in infected macrophages. One of the deubiquitinases identified was USP8, which was downregulated upon Salmonella infection. Inhibition of USP8 was associated with a decrease in bacterial survival within macrophages, and it was found to play a distinct role in regulating autophagy during Salmonella infection. The inhibition of USP8 led to the downregulation of the p62 autophagy adaptor.DiscussionThe findings of this study suggest a novel role of USP8 in regulating autophagy flux, which restricts intracellular bacteria, particularly during Salmonella infection.

Ubiquitin-specific protease 8 controls B-cell proteostasis and survival representing a target in multiple myeloma

“…Somatic mutations in the exon encoding the 14-3-3 binding motif of USP8 are associated with Cushing's disease (CD) leading to the stabilization of the EGFR in ACTH-secreting pituitary adenomas 6,7 . USP8 was also associated with autophagy and mitophagy regulation 3,8,9 , and has been implicated in the progression of many cancer types including effects on the tumor microenvironment via regulation of PD-L1 and regulation of TGF-β signaling and inflammatory responses [10][11][12][13] .…”