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 PPARγ, HK2 and SIRT6 expression was observed upon PMA induced monocyte differentiation. While PPARγ 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 β-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. SIRT6-HK2 crosstalk regulates autophagy responses during monocyte differentiation. Graphical abstract depicting the role of HK2 in the regulation of monocyte differentiation and function. LND denotes Lonidamine. [Display omitted] •SIRT6 negatively regulates HK2 expression in differentiating monocytes.•Inhibition of HK2 promotes autophagy dependent monocyte differentiation.•Acquisition of macrophage M1 vs M2 phenotype is HK2 dependent.•HK2 also regulates cytoskeletal architecture and cytokine milieu.