Beyond neurotransmission: the roles of serotonylation in physiological and pathological processes

Serotonin, also known as 5-HT, is a classical neurotransmitter produced both in the nervous system and in non-nervous system. Its involvement in various fundamental physiological processes and pathogenic conditions is significant, as it binds to a diverse array of functionally distinct receptors. Apart from binding to 5-HT receptors and activating downstream signaling cascades, recent studies have revealed a novel posttranslational modification named serotonylation, where serotonin is re-taken up by serotonin transporter and is covalently attached to target proteins ranging from histone proteins to nonhistone proteins. Transglutaminases (TGMs), especially TGM2, catalyze serotonylation through the transfer of serotonin to the glutamine residues of target proteins. This review aims to investigate recent progresses in understanding the involvement of serotonylation in physiological and pathological processes. In addition, this review emphasizes how to target serotonylation as a therapeutic strategy for disease management.