MTR4 methylation-dependent degradation activates mTORC1 signaling to promote glioma cell survival under methionine starvation.

Methionine is an essential amino acid for the human body. Understanding how tumor cells adjust their signaling networks to evade apoptosis and sustain proliferation in a methionine starvation tumor microenvironment is a significant scientific question that warrants in-depth investigation. This study aims to explore the response mechanisms of glioma under methionine starvation conditions, thereby providing a theoretical foundation for the development of novel therapeutic strategies for glioma. To investigate the response of glioma cells to a methionine starvation environment, we established methionine-starvation-tolerant cells. Our findings indicate that mRNA transporter 4 (MTR4) plays a crucial role in cellular adaptation to methionine starvation. This study employed various experimental approaches, including Western blotting, immunohistochemical staining, and colony formation assays, to validate the expression mechanism of MTR4 under methionine starvation conditions. Furthermore, transfection, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and cytoplasmic-nuclear fractionation techniques were utilized to explore the regulatory mechanism of MTR4 on solute carrier family 1 member 5 (SLC1A5). In response to methionine starvation, glioma cells exhibited a time-dependent activation of the mTOR signaling pathway. Transcriptomic analysis revealed a high expression of the methionine transporter SLC1A5, which is regulated at the mRNA level by the nuclear export factor MTR4. Under conditions of methionine starvation, MTR4 undergoes methylation, leading to its ubiquitination. Lysine Methyltransferase 2B (KMT2B) has been identified as the methyltransferase responsible for the methylation of MTR4. In summary, we propose that under conditions of methionine starvation, the enhanced methylation of MTR4 promotes its ubiquitin-mediated degradation. This process facilitates the nuclear export and expression of amino acid transporter mRNA, such as SLC1A5, leading to increased amino acid uptake, activation of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway, and ultimately ensuring the survival of glioma cells. Our study provides new insights into the molecular mechanisms underlying glioma cell adaptation to methionine starvation. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00726-025-03495-w.