Singh Ankita, Sen Ellora
National Brain Research Centre, Manesar, Haryana 122051, India.
National Brain Research Centre, Manesar, Haryana 122051, India.
Exp Cell Res. 2017 Nov 15;360(2):365-374. doi: 10.1016/j.yexcr.2017.09.028. Epub 2017 Sep 19.
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.
新出现的证据表明自噬对分化有影响，但单核细胞分化过程中代谢重塑与自噬之间潜在的分子联系仍不清楚。在佛波酯（PMA）诱导单核细胞分化后，观察到过氧化物酶体增殖物激活受体γ（PPARγ）、己糖激酶2（HK2）和沉默信息调节因子6（SIRT6）的表达增加。虽然PPARγ正向调节HK2和SIRT6的表达，但后者作为HK2的负调节因子。这些代谢调节因子表达的变化伴随着葡萄糖摄取减少以及β-连环蛋白/翼状螺旋转录因子（Wnt）途径的强效拮抗剂Chibby增加。敲低Chibby可消除PMA诱导的分化。用氯尼达明或小干扰RNA（siRNA）抑制HK2可进一步提高PMA诱导的Chibby、线粒体活性氧（ROS）、TP53诱导糖酵解和凋亡调节因子（TIGAR）以及微管相关蛋白1轻链3II（LC3II）水平；与HK2相比，siRNA介导的SIRT6敲低表现出相反的效果。值得注意的是，抑制自噬会增加HK2、降低Chibby水平和CD33表达。此外，发现PMA诱导的细胞骨架结构蛋白、趋化因子受体4（CXCR4）表达、吞噬作用、巨噬细胞表型的获得以及促炎介质的释放均依赖于HK2。总的来说，我们的研究结果突出了SIRT6和HK2在调节自噬驱动的单核细胞分化方面以前未知的相互影响。
