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Pyruvate kinase M2 is requisite for Th1 and Th17 differentiation

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Title: Pyruvate kinase M2 is requisite for Th1 and Th17 differentiation
Authors: Kono, Michihito Browse this author →KAKEN DB
Maeda, Kayaho Browse this author
Stocton-Gavanescu, Irina Browse this author
Pan, Wenliang Browse this author
Umeda, Masataka Browse this author
Katsuyama, Eri Browse this author
Burbano, Catalina Browse this author
Orite, Seo Yeon K. Browse this author
Vukelic, Milena Browse this author
Tsokos, Maria G. Browse this author
Yoshida, Nobuya Browse this author
Tsokos, George C. Browse this author
Issue Date: 20-Jun-2019
Publisher: American Society for Clinical Investigation
Journal Title: JCI Insight
Volume: 4
Issue: 12
Start Page: e127395
Publisher DOI: 10.1172/jci.insight.127395
PMID: 31217348
Abstract: Th1 and Th17 are important in the pathogenesis of autoimmune diseases and they depend on glycolysis as a source of energy. T cell antigen receptor signaling phosphorylates a serine/threonine kinase, calcium/calmodulin-dependent protein kinase IV (CaMK4), and promotes glycolysis. Based on these findings we hypothesized that CaMK4 promotes glycolysis. Camk4-deficient CD4(+) T cells and cells treated with a CaMK4 inhibitor had less glycolysis compared with their counterparts. Pull-down of CaMK4 and mass spectrometry identified pyruvate kinase muscle isozyme (PKM), the final rate-limiting enzyme in glycolysis, as a binding partner. Coimmunoprecipitation and Western blotting showed that CaMK4 interacts directly with PKM2. Camk4-deficient CD4(+) T cells displayed decreased pyruvate kinase activity. Silencing or pharmacological inhibition of PKM2 reduced glycolysis and in vitro differentiation to Th1 and Th17 cells, while PKM2 overexpression restored Th17 cell differentiation. Treatment with a PKM2 inhibitor ameliorated experimental autoimmune encephalomyelitis and CD4(+) T cells treated with PKM2 inhibitor or Pkm2-shRNA caused limited disease activity in an adoptive cell transfer model of experimental autoimmune encephalomyelitis. Our data demonstrate that CaMK4 binds to PKM2 and promotes its activity, which is requisite for Th1 and Th17 differentiation in vitro and in vivo. PKM2 represents a therapeutic target for T cell-dependent autoimmune diseases.
Type: article
URI: http://hdl.handle.net/2115/75001
Appears in Collections:医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

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