MTHFD2 reprograms macrophage polarization by inhibiting PTEN

• Published in: Cell reports (Cambridge) 2023-05, Vol.42 (5), p.112481-112481, Article 112481
• Main Authors: Shang, Man, Ni, Lina, Shan, Xiao, Cui, Yan, Hu, Penghui, Ji, Zemin, Shen, Long, Zhang, Yanan, Zhou, Jinxue, Bing Chen, Wang, Ting, Yu, Qiujing
• Format: Article
• Language: English
• Subjects: CP: Immunology; Humans; Interferon-gamma - metabolism; Interferon-gamma - pharmacology; Interleukin-4 - metabolism; macrophage polarization; Macrophages - metabolism; MTHFD2; Neoplasms - metabolism; Protein Binding; PTEN; PTEN Phosphohydrolase - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112481

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. [Display omitted] •MTHFD2 suppresses M(IFN-γ) but enhances M(IL-4) polarization both in vitro and in vivo•MTHFD2 interacts with PTEN to suppress PTEN’s PIP3 phosphatase activity•MTHFD2 (aa 215–225) directly targets PTEN catalytic center (aa 118–141)•Residue D168 of MTHFD2 is also critical for regulating MTHFD2-PTEN interaction MTHFD2 is a one-carbon enzyme that is highly induced in a variety of tumors to meet high biosynthetic demand. Shang et al. show that, through interacting with PTEN to inhibit PTEN’s PIP3 phosphatase activity, MTHFD2 reprograms macrophage functionality by inhibiting M(IFN-γ) while promoting M(IL-4) polarization.