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USP7- and PRMT5-dependent G3BP2 stabilization drives de novo lipogenesis and tumorigenesis of HNSC

GTPase-activating protein-binding protein 2 (G3BP2) is a key stress granule-associated RNA-binding protein responsible for the formation of stress granules (SGs). Hyperactivation of G3BP2 is associated with various pathological conditions, especially cancers. Emerging evidence indicates that post-tr...

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Autores principales: Wang, Nan, Li, Tianzi, Liu, Wanyu, Lin, Jinhua, Zhang, Ke, Li, Zhenhao, Huang, Yanfei, Shi, Yufei, Xu, Meilan, Liu, Xuekui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9988876/
https://www.ncbi.nlm.nih.gov/pubmed/36878903
http://dx.doi.org/10.1038/s41419-023-05706-2
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author Wang, Nan
Li, Tianzi
Liu, Wanyu
Lin, Jinhua
Zhang, Ke
Li, Zhenhao
Huang, Yanfei
Shi, Yufei
Xu, Meilan
Liu, Xuekui
author_facet Wang, Nan
Li, Tianzi
Liu, Wanyu
Lin, Jinhua
Zhang, Ke
Li, Zhenhao
Huang, Yanfei
Shi, Yufei
Xu, Meilan
Liu, Xuekui
author_sort Wang, Nan
collection PubMed
description GTPase-activating protein-binding protein 2 (G3BP2) is a key stress granule-associated RNA-binding protein responsible for the formation of stress granules (SGs). Hyperactivation of G3BP2 is associated with various pathological conditions, especially cancers. Emerging evidence indicates that post-translational modifications (PTMs) play critical roles in gene transcription, integrate metabolism and immune surveillance. However, how PTMs directly regulate G3BP2 activity is lacking. Here, our analyses identify a novel mechanism that PRMT5-mediated G3BP2-R468me2 enhances the binding to deubiquitinase USP7, which ensures the deubiquitination and stabilization of G3BP2. Mechanistically, USP7- and PRMT5-dependent G3BP2 stabilization consequently guarantee robust ACLY activation, which thereby stimulating de novo lipogenesis and tumorigenesis. More importantly, USP7-induced G3BP2 deubiquitination is attenuated by PRMT5 depletion or inhibition. PRMT5-activity dependent methylation of G3BP2 is required for its deubiquitination and stabilization by USP7. Consistently, G3BP2, PRMT5 and G3BP2 R468me2 protein levels were found positively correlated in clinical patients and associated with poor prognosis. Altogether, these data suggest that PRMT5-USP7-G3BP2 regulatory axis serves as a lipid metabolism reprogramming mechanism in tumorigenesis, and unveil a promising therapeutic target in the metabolic treatment of head and neck squamous carcinoma.
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spelling pubmed-99888762023-03-08 USP7- and PRMT5-dependent G3BP2 stabilization drives de novo lipogenesis and tumorigenesis of HNSC Wang, Nan Li, Tianzi Liu, Wanyu Lin, Jinhua Zhang, Ke Li, Zhenhao Huang, Yanfei Shi, Yufei Xu, Meilan Liu, Xuekui Cell Death Dis Article GTPase-activating protein-binding protein 2 (G3BP2) is a key stress granule-associated RNA-binding protein responsible for the formation of stress granules (SGs). Hyperactivation of G3BP2 is associated with various pathological conditions, especially cancers. Emerging evidence indicates that post-translational modifications (PTMs) play critical roles in gene transcription, integrate metabolism and immune surveillance. However, how PTMs directly regulate G3BP2 activity is lacking. Here, our analyses identify a novel mechanism that PRMT5-mediated G3BP2-R468me2 enhances the binding to deubiquitinase USP7, which ensures the deubiquitination and stabilization of G3BP2. Mechanistically, USP7- and PRMT5-dependent G3BP2 stabilization consequently guarantee robust ACLY activation, which thereby stimulating de novo lipogenesis and tumorigenesis. More importantly, USP7-induced G3BP2 deubiquitination is attenuated by PRMT5 depletion or inhibition. PRMT5-activity dependent methylation of G3BP2 is required for its deubiquitination and stabilization by USP7. Consistently, G3BP2, PRMT5 and G3BP2 R468me2 protein levels were found positively correlated in clinical patients and associated with poor prognosis. Altogether, these data suggest that PRMT5-USP7-G3BP2 regulatory axis serves as a lipid metabolism reprogramming mechanism in tumorigenesis, and unveil a promising therapeutic target in the metabolic treatment of head and neck squamous carcinoma. Nature Publishing Group UK 2023-03-06 /pmc/articles/PMC9988876/ /pubmed/36878903 http://dx.doi.org/10.1038/s41419-023-05706-2 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Wang, Nan
Li, Tianzi
Liu, Wanyu
Lin, Jinhua
Zhang, Ke
Li, Zhenhao
Huang, Yanfei
Shi, Yufei
Xu, Meilan
Liu, Xuekui
USP7- and PRMT5-dependent G3BP2 stabilization drives de novo lipogenesis and tumorigenesis of HNSC
title USP7- and PRMT5-dependent G3BP2 stabilization drives de novo lipogenesis and tumorigenesis of HNSC
title_full USP7- and PRMT5-dependent G3BP2 stabilization drives de novo lipogenesis and tumorigenesis of HNSC
title_fullStr USP7- and PRMT5-dependent G3BP2 stabilization drives de novo lipogenesis and tumorigenesis of HNSC
title_full_unstemmed USP7- and PRMT5-dependent G3BP2 stabilization drives de novo lipogenesis and tumorigenesis of HNSC
title_short USP7- and PRMT5-dependent G3BP2 stabilization drives de novo lipogenesis and tumorigenesis of HNSC
title_sort usp7- and prmt5-dependent g3bp2 stabilization drives de novo lipogenesis and tumorigenesis of hnsc
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9988876/
https://www.ncbi.nlm.nih.gov/pubmed/36878903
http://dx.doi.org/10.1038/s41419-023-05706-2
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