JAK2V617F Mutation Promoted IL-6 Production and Glycolysis via Mediating PKM1 Stabilization in Macrophages
Rongqing Li, Na Sun, Xin Chen, Xueqin Li, Jie Zhao, Wanpeng Cheng, Hui Hua, Masahiko Fukatsu, Hirotaka Mori, Hiroshi Takahashi, Hiroshi Ohkawara, Miwa Fukami, Masatoshi Okamoto, Yoichi Hamazaki, Kuiyang Zheng, Jing Yang, Takayuki Ikezoe
Abstract
A substitution mutation of valine to phenylalanine at codon encoding position 617 of the Janus kinase 2 ( JAK2 ) gene ( JAK2 V617F ) has been detected in myeloid cells of some individuals with higher levels of proinflammatory cytokine production such as interleukin (IL)-6. However, the mechanisms by which JAK2 V617F mutation mediating those cytokines remain unclear. We, therefore, established JAK2 V617F -expressing murine macrophages ( JAK2 V617F macrophages) and found that the levels of p-STAT3 were markedly elevated in JAK2 V617F macrophages in association with an increase in IL-6 production. However, inhibition of STAT3 by C188-9 significantly decreased the production of IL-6. Furthermore, the JAK2 V617F mutation endowed macrophages with an elevated glycolytic phenotype in parallel with aberrant expression of PKM1. Interestingly, silencing of PKM1 inactivated STAT3 in parallel with reduced IL-6 production. In contrast, ectopic expression of PKM1 elevated IL-6 production via STAT3 activation. Importantly, the JAK2 V617F mutation contributed to PKM1 protein stabilization via blockade of lysosomal-dependent degradation via chaperone-mediated autophagy (CMA), indicating that the JAK2 V617F mutation could protect PKM1 from CMA-mediated degradation, leading to activation of STAT3 and promoting IL-6 production.