A GAPDH serotonylation system couples CD8+T cell glycolytic metabolism to antitumor immunity

Apart from the canonical serotonin (5-hydroxytryptamine [5 -HT]) -receptor signaling transduction pattern, 5 -HT -involved post -translational serotonylation has recently been noted. Here, we report a glyceraldehyde-3-phosphate dehydrogenase (GAPDH) serotonylation system that promotes the glycolytic metabolism and antitumor immune activity of CD8+ T cells. Tissue transglutaminase 2 (TGM2) transfers 5 -HT to GAPDH glutamine 262 and catalyzes the serotonylation reaction. Serotonylation supports the cytoplasmic localization of GAPDH, which induces a glycolytic metabolic shift in CD8+ T cells and contributes to antitumor immunity. CD8+ T cells accumulate intracellular 5 -HT for serotonylation through both synthesis by tryptophan hydroxylase 1 (TPH1) and uptake from the extracellular compartment via serotonin transporter (SERT). Monoamine oxidase A (MAOA) degrades 5 -HT and acts as an intrinsic negative regulator of CD8+ T cells. The adoptive transfer of 5 -HT -producing TPH1-overexpressing chimeric antigen receptor T (CAR -T) cells induced a robust antitumor response. Our findings expand the known range of neuroimmune interaction patterns by providing evidence of receptor -independent serotonylation post -translational modification.