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Ghosh, S and Gupta, P and Sen, E (2016) TNFα driven HIF-1α-hexokinase II axis regulates MHC-I cluster stability through actin cytoskeleton. Exp Cell Res, 340 (1). pp. 116-124.

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Abstract

Hypoxia-inducible Factor-1α (HIF-1α)-regulated expression of Hexokinase-II (HKII) remains a cornerstone in the maintenance of high metabolic demands subserving various pro-tumor functions including immune evasion in gliomas. Since inflammation-induced HIF-1α regulates Major Histocompatibility Complex class I (MHC-I) gene expression, and as cytoskeletal dynamics affect MHC-I membrane clusters, we investigated the involvement of HIF-1α-HKII axis in Tumor Necrosis Factor-α (TNFα)-mediated MHC-I membrane cluster stability in glioma cells and the involvement of actin cytoskeleton in the process. TNFα increased the clustering and colocalization of MHC-I with cortical actin in a HIF-1α dependent manner. siRNA mediated knockdown of HIF-1α as well as enzymatic inhibition of HK II by Lonidamine, delocalized mitochondrially bound HKII. This altered subcellular HKII localization affected TNFα-induced cofilin activation and actin turnover, as pharmacological inhibition of HKII by Lonidamine decreased Actin-related protein 2 (ARP2)/cofilin interaction. Photobleaching studies revealed destabilization of TNFα- induced stable MHC-I membrane clusters in the presence of Lonidamine and ARP2 inhibitor CK666. This work highlights how TNFα triggers a previously unknown function of metabolic protein HKII to influence an immune related outcome. Our study establishes the importance of inflammation induced HIF-1α in integrating two crucial components- the metabolic and immune, through reorganization of cytoskeleton.

Item Type: Article
Subjects: Neurodegenerative Disorders
Neuro-Oncological Disorders
Neurocognitive Processes
Neuronal Development and Regeneration
Informatics and Imaging
Genetics and Molecular Biology
Depositing User: Dr. D.D. Lal
Date Deposited: 13 Jul 2017 06:30
Last Modified: 10 May 2018 06:30
URI: http://nbrc.sciencecentral.in/id/eprint/223

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