JAK2V617F Mutation Promoted IL-6 Production and Glycolysis via Mediating PKM1 Stabilization in Macrophages.

Rongqing Li,Masahiko Fukatsu,Hiroshi Takahashi,Jie Zhao,Hui Hua,Na Sun,Miwa Fukami,Hiroshi Ohkawara,Jing Yang,Kuiyang Zheng,Wanpeng Cheng,Xueqin Li,Yoichi Hamazaki,Hirotaka Mori,Takayuki Ikezoe,Xin Chen,Masatoshi Okamoto

doi:10.3389/fimmu.2020.589048

Rongqing Li, Masahiko Fukatsu + Show 15 more

Open Access

https://doi.org/10.3389/fimmu.2020.589048

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Abstract

A substitution mutation of valine to phenylalanine at codon encoding position 617 of the Janus kinase 2 (JAK2) gene (JAK2V617F) 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 JAK2V617F mutation mediating those cytokines remain unclear. We, therefore, established JAK2V617F-expressing murine macrophages (JAK2V617F macrophages) and found that the levels of p-STAT3 were markedly elevated in JAK2V617F 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 JAK2V617F 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 JAK2V617F mutation contributed to PKM1 protein stabilization via blockade of lysosomal-dependent degradation via chaperone-mediated autophagy (CMA), indicating that the JAK2V617F mutation could protect PKM1 from CMA-mediated degradation, leading to activation of STAT3 and promoting IL-6 production.

Highlights

Janus kinase 2 (JAK2) is a non-receptor tyrosine kinase that activates signal transduction and activator of transcription (STAT) and mediates cytokine signaling
Exposure of JAK2V617F-expressing myeloid cells to LPS produced greater amounts of IL-6 than that produced by control cells, which was consistent with the current study results (Figure 1)
Another study showed that the transplantation of JAK2V617F-expressing hematopoietic stem cells enhanced the formation of atherosclerotic lesions in lipoprotein receptor knockout mice

Summary

Introduction

JAK2 is a non-receptor tyrosine kinase that activates signal transduction and activator of transcription (STAT) and mediates cytokine signaling. Erythropoietin binds to its receptor which in turn phosphorylates JAK2/STAT3 and regulates erythropoiesis [1]. JAK2V617F mutation confers ligand-independent activation of STATs [3]. Transplantation of JAK2V617F -expressing hematopoietic cells resulted in erythrocytosis in a murine model [4]. The JAK2V617F mutation was detected in individuals who developed Budd-Chiari syndrome, a potentially lethal thrombotic disease, even though they did not have any thrombotic risk factors or complete blood cell count abnormalities [5]. Veno-occlusive disease was more frequently noted in individuals with myelodysplastic syndromes harboring the JAK2V617F mutation than in those without the mutation [6]

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