TNFα driven HIF-1α-Hexokinase II axis regulates MHC-I cluster stability through actin cytoskeleton.

TNFα driven HIF-1α-Hexokinase II axis regulates MHC-I cluster stability through actin cytoskeleton. Exp Cell Res. 2015 Nov 17; Authors: Ghosh S, Gupta P, Sen E 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 functio...
Source: Experimental Cell Research - Category: Cytology Authors: Tags: Exp Cell Res Source Type: research