Reciprocal role of SIRT6 and Hexokinase 2 in the regulation of autophagy driven monocyte differentiation

Emerging evidences suggest the impact of autophagy on differentiation but the underlying molecular links between metabolic restructuring and autophagy during monocyte differentiation remain elusive. An increase in PPAR gamma, HK2 and SIRT6 expression was observed upon PMA induced monocyte differentiation. While PPAR gamma positively regulated HK2 and SIRT6 expression, the latter served as a negative regulator of HK2. Changes in expression of these metabolic modelers were accompanied by decreased glucose uptake and increase in Chibby, a potent antagonist of beta-catenin/Wnt pathway. Knockdown of Chibby abrogated PMA induced differentiation. While inhibition of HK2 either by Lonidamine or siRNA further elevated PMA induced Chibby, mitochondrial ROS, TIGAR and LC3II levels; siRNA mediated knock-down of SIRT6 exhibited contradictory effects as compared to HK2. Notably, inhibition of autophagy increased HK2, diminished Chibby level and CD33 expression. In addition, PMA induced expression of cytoskeletal architectural proteins, CXCR4, phagocytosis, acquisition of macrophage phenotypes and release of pro-inflammatory mediators was found to be HK2 dependent. Collectively, our findings highlight the previously unknown reciprocal influence of SIRT6 and HK2 in regulating autophagy driven monocyte differentiation.