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Analyses of high-throughput screening and biochemical examines reveal that the natural compound PGG employs a potent “dual-mechanism ” inhibition on MAT2A. It not only blocks the enzyme’s activity but also tags it for destruction via the SMURF1-mediated ubiquitin-proteasome pathway. Both chemical inhibiting MAT2A using PGG and genetically ablating Mat2a trigger pyroptosis—a form of immunogenic cell death—in both macrophages and tumor cells by activating GSDME, resulting in an anti-tumor immune response effectively and suppressing tumor progression.
Credit: Fudan University Press
Pyroptosis is an inflammatory form of programmed cell death. Pyroptotic cells rupture and release intracellular contents to trigger inflammation and ignite antitumor immunity. However, the metabolic signals that govern this process have remained largely unknown.
To investigate the metabolic underpinning of pyroptosis, a research team led by Professor Qun-Ying Lei at Shanghai Medical College, Fudan University, conducted an untargeted metabolomic profiling analysis of primary mouse bone marrow-derived macrophages (BMDMs) treated with lipopolysaccharide (LPS) and either ATP or nigericin (Ni) to induce pyroptosis. The researchers found that MAT2A-mediated methionine metabolism plays a critical role in regulating this process.
To further validate this finding, the team generated myeloid cell-specific Mat2a conditional knockout mice. They observed that Mat2a deletion induces pyroptosis in macrophages, a process that is dependent on the cleavage and activation of GSDME, rather than the classical GSDMD pathway.
Different MAT2A inhibitors are in clinical trials. Nevertheless, these inhibitors could trigger upregulation of MAT2A protein expression, potentially leading to resistance. In this study, the team identified the natural compound 1,2,3,4,6-O-pentagalloylglucose (PGG) as a MAT2A inhibitor through high-throughput screening. Intriguingly, unlike the developed MAT2A inhibitors, which only inhibit MAT2A activity, PGG kills two birds with one stone, inhibiting MAT2A enzymatic activity and promoting its protein degradation. This dual-mechanism inhibitor effect of PGG on MAT2A provide promising way to overcome the potential resistance caused by feedback upregulation of MAT2A protein level with the current MAT2A inhibitors.
“This study systematically reveals the critical role of MAT2A—a key enzyme in methionine metabolism—in regulating pyroptosis and anti-tumor immunity,” said Professor Lei. “Furthermore, we have identified the natural small molecule PGG as a novel lead compound for MAT2A inhibition, offering a promising new strategy for cancer immunotherapy.”
Journal
Science China Life Sciences
Method of Research
Experimental study
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