MTHFD2 reprograms macrophage polarization by inhibiting PTEN
| Autor: | Man Shang, Lina Ni, Xiao Shan, Yan Cui, Penghui Hu, Zemin Ji, Long Shen, Yanan Zhang, Jinxue Zhou, Bing Chen, Ting Wang, Qiujing Yu |
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| Jazyk: | angličtina |
| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | Cell Reports, Vol 42, Iss 5, Pp 112481- (2023) |
| Druh dokumentu: | article |
| ISSN: | 2211-1247 81267290 |
| DOI: | 10.1016/j.celrep.2023.112481 |
| Popis: | Summary: 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. |
| Databáze: | Directory of Open Access Journals |
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