2. Academic Validation
  3. MTHFD2 reprograms macrophage polarization by inhibiting PTEN

MTHFD2 reprograms macrophage polarization by inhibiting PTEN

  • Cell Rep. 2023 May 5;42(5):112481. doi: 10.1016/j.celrep.2023.112481.
Man Shang 1,  Lina Ni 1,  Xiao Shan 1,  Yan Cui 1,  Penghui Hu 1,  Zemin Ji 1,  Long Shen 1,  Yanan Zhang 1,  Jinxue Zhou 2,  Bing Chen 3,  Ting Wang 4,  Qiujing Yu 5
Affiliations

Affiliations

  • 1 Tianjin Institute of Immunology, Division of Infectious Disease, Second Hospital of Tianjin Medical University, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, Tianjin Medical University, Tianjin, 300070, China.
  • 2 Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China.
  • 3 Division of Infectious Disease, Second Hospital of Tianjin Medical University, Tianjin 300070, China. Electronic address: [email protected].
  • 4 The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, Tianjin Medical University, Tianjin 300070, China. Electronic address: [email protected].
  • 5 Tianjin Institute of Immunology, Division of Infectious Disease, Second Hospital of Tianjin Medical University, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, Tianjin Medical University, Tianjin, 300070, China. Electronic address: [email protected].
PMID: 37149861 DOI: 10.1016/j.celrep.2023.112481
Abstract

The one-carbon metabolism Enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is involved in the regulation of tumor oncogenesis and immune cell functions, but whether it can contribute to macrophage polarization remains elusive. Here, we show that MTHFD2 suppresses polarization of interferon-γ-activated macrophages (M(IFN-γ)) but enhances that of interleukin-4-activated macrophages (M(IL-4)) both in vitro and in vivo. Mechanistically, MTHFD2 interacts with Phosphatase and tensin homolog (PTEN) to suppress PTEN's phosphatidylinositol 3,4,5-trisphosphate (PIP3) Phosphatase activity and enhance downstream Akt activation, independent of the N-terminal mitochondria-targeting signal of MTHFD2. MTHFD2-PTEN interaction is promoted by IL-4 but not IFN-γ. Furthermore, amino acid residues (aa 215-225) of MTHFD2 directly target PTEN catalytic center (aa 118-141). Residue D168 of MTHFD2 is also critical for regulating PTEN's PIP3 Phosphatase activity by affecting MTHFD2-PTEN interaction. Our study suggests a non-metabolic function of MTHFD2 by which MTHFD2 inhibits PTEN activity, orchestrates macrophage polarization, and alters macrophage-mediated immune responses.

Keywords

CP: Immunology; MTHFD2; PTEN; macrophage polarization.

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