JAK2V617F Mutation Promoted IL-6 Production and Glycolysis via Mediating PKM1 Stabilization in Macrophages
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 whic...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-02-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2020.589048/full |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Rongqing Li Rongqing Li Rongqing Li Na Sun Na Sun Na Sun Xin Chen Xin Chen Xueqin Li Xueqin Li Jie Zhao Jie Zhao Wanpeng Cheng Wanpeng Cheng Hui Hua Hui Hua Masahiko Fukatsu Hirotaka Mori Hiroshi Takahashi Hiroshi Ohkawara Miwa Fukami Masatoshi Okamoto Yoichi Hamazaki Kuiyang Zheng Kuiyang Zheng Jing Yang Jing Yang Takayuki Ikezoe |
| spellingShingle |
Rongqing Li Rongqing Li Rongqing Li Na Sun Na Sun Na Sun Xin Chen Xin Chen Xueqin Li Xueqin Li Jie Zhao Jie Zhao Wanpeng Cheng Wanpeng Cheng Hui Hua Hui Hua Masahiko Fukatsu Hirotaka Mori Hiroshi Takahashi Hiroshi Ohkawara Miwa Fukami Masatoshi Okamoto Yoichi Hamazaki Kuiyang Zheng Kuiyang Zheng Jing Yang Jing Yang Takayuki Ikezoe JAK2V617F Mutation Promoted IL-6 Production and Glycolysis via Mediating PKM1 Stabilization in Macrophages Frontiers in Immunology JAK2V617F glycolysis PKM1 STAT3 IL-6 |
| author_facet |
Rongqing Li Rongqing Li Rongqing Li Na Sun Na Sun Na Sun Xin Chen Xin Chen Xueqin Li Xueqin Li Jie Zhao Jie Zhao Wanpeng Cheng Wanpeng Cheng Hui Hua Hui Hua Masahiko Fukatsu Hirotaka Mori Hiroshi Takahashi Hiroshi Ohkawara Miwa Fukami Masatoshi Okamoto Yoichi Hamazaki Kuiyang Zheng Kuiyang Zheng Jing Yang Jing Yang Takayuki Ikezoe |
| author_sort |
Rongqing Li |
| title |
JAK2V617F Mutation Promoted IL-6 Production and Glycolysis via Mediating PKM1 Stabilization in Macrophages |
| title_short |
JAK2V617F Mutation Promoted IL-6 Production and Glycolysis via Mediating PKM1 Stabilization in Macrophages |
| title_full |
JAK2V617F Mutation Promoted IL-6 Production and Glycolysis via Mediating PKM1 Stabilization in Macrophages |
| title_fullStr |
JAK2V617F Mutation Promoted IL-6 Production and Glycolysis via Mediating PKM1 Stabilization in Macrophages |
| title_full_unstemmed |
JAK2V617F Mutation Promoted IL-6 Production and Glycolysis via Mediating PKM1 Stabilization in Macrophages |
| title_sort |
jak2v617f mutation promoted il-6 production and glycolysis via mediating pkm1 stabilization in macrophages |
| publisher |
Frontiers Media S.A. |
| series |
Frontiers in Immunology |
| issn |
1664-3224 |
| publishDate |
2021-02-01 |
| description |
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. |
| topic |
JAK2V617F glycolysis PKM1 STAT3 IL-6 |
| url |
https://www.frontiersin.org/articles/10.3389/fimmu.2020.589048/full |
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doaj-f2e7910c66fd46ee91f514e64761a9e62021-02-08T04:23:33ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-02-011110.3389/fimmu.2020.589048589048JAK2V617F Mutation Promoted IL-6 Production and Glycolysis via Mediating PKM1 Stabilization in MacrophagesRongqing Li0Rongqing Li1Rongqing Li2Na Sun3Na Sun4Na Sun5Xin Chen6Xin Chen7Xueqin Li8Xueqin Li9Jie Zhao10Jie Zhao11Wanpeng Cheng12Wanpeng Cheng13Hui Hua14Hui Hua15Masahiko Fukatsu16Hirotaka Mori17Hiroshi Takahashi18Hiroshi Ohkawara19Miwa Fukami20Masatoshi Okamoto21Yoichi Hamazaki22Kuiyang Zheng23Kuiyang Zheng24Jing Yang25Jing Yang26Takayuki Ikezoe27Jiangsu Province Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, ChinaDepartment of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, ChinaThe Department of Hematology, Fukushima Medical University, Fukushima, JapanJiangsu Province Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, ChinaDepartment of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, ChinaThe Department of Hematology, Fukushima Medical University, Fukushima, JapanJiangsu Province Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, ChinaDepartment of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, ChinaJiangsu Province Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, ChinaDepartment of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, ChinaJiangsu Province Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, ChinaDepartment of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, ChinaJiangsu Province Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, ChinaDepartment of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, ChinaJiangsu Province Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, ChinaDepartment of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, ChinaThe Department of Hematology, Fukushima Medical University, Fukushima, JapanThe Department of Hematology, Fukushima Medical University, Fukushima, JapanThe Department of Hematology, Fukushima Medical University, Fukushima, JapanThe Department of Hematology, Fukushima Medical University, Fukushima, JapanThe Department of Hematology, Fukushima Medical University, Fukushima, JapanDepartment of Hematology, YUASA Foundation Jusendo General Hospital, Koriyama, JapanDepartment of Hematology, Iwaki City Medical Center, Iwaki, JapanJiangsu Province Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, ChinaDepartment of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, ChinaJiangsu Province Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, ChinaDepartment of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, ChinaThe Department of Hematology, Fukushima Medical University, Fukushima, JapanA 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.https://www.frontiersin.org/articles/10.3389/fimmu.2020.589048/fullJAK2V617FglycolysisPKM1STAT3IL-6 |