Proteomic analysis reveals USP7 as a novel regulator of palmitic acid-induced hepatocellular carcinoma cell death.

Autor: Saha S; Functional Proteomics Laboratory, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, 121001, India., Verma R; Virology Laboratory, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, 121001, India., Kumar C; Laboratory of Cellular Dynamics, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, 121001, India., Kumar B; Functional Proteomics Laboratory, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, 121001, India., Dey AK; Functional Proteomics Laboratory, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, 121001, India., Surjit M; Virology Laboratory, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, 121001, India., Mylavarapu SVS; Laboratory of Cellular Dynamics, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, 121001, India., Maiti TK; Functional Proteomics Laboratory, Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, 121001, India. tkmaiti@rcb.res.in.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2022 Jun 22; Vol. 13 (6), pp. 563. Date of Electronic Publication: 2022 Jun 22.
DOI: 10.1038/s41419-022-05003-4
Abstrakt: Nutrient surplus and consequent free fatty acid accumulation in the liver cause hepatosteatosis. The exposure of free fatty acids to cultured hepatocyte and hepatocellular carcinoma cell lines induces cellular stress, organelle adaptation, and subsequent cell death. Despite many studies, the mechanism associated with lipotoxicity and subsequent cell death still remains poorly understood. Here, we have used the proteomics approach to circumvent the mechanism for lipotoxicity using hepatocellular carcinoma cells as a model. Our quantitative proteomics data revealed that ectopic lipids accumulation in cells severely affects the ubiquitin-proteasomal system. The palmitic acid (PA) partially lowered the expression of deubiquitinating enzyme USP7 which subsequently destabilizes p53 and promotes mitotic entry of cells. Our global phosphoproteomics analysis also provides strong evidence of an altered cell cycle checkpoint proteins' expression that abrogates early G2/M checkpoints recovery with damaged DNA and induced mitotic catastrophe leading to hepatocyte death. We observe that palmitic acid prefers apoptosis-inducing factor (AIF) mediated cell death by depolarizing mitochondria and translocating AIF to the nucleus. In summary, the present study provides evidence of PA-induced hepatocellular death mediated by deubiquitinase USP7 downregulation and subsequent mitotic catastrophe.
(© 2022. The Author(s).)
Databáze: MEDLINE
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