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
  • 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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