Malonate promotes CD8⁺ T cell memory formation via protein malonylation

Protein malonylation represents a recently identified posttranslational modification whose role in CD8⁺ T cell differentiation and functionality remains incompletely understood. In this study, we demonstrate that enhancing protein malonylation through sodium malonate (SM) treatment promotes CD8⁺ T cell memory formation in response to bacterial infection, subsequently potentiating recall responses. Comparative metabolomic analysis between SM-treated and control CD8⁺ T cells revealed significant metabolic alterations associated with protein malonylation. We present the first comprehensive proteomic analysis of lysine malonylation in murine CD8⁺ T cells, identifying 77 malonylation sites across 64 proteins involved in diverse cellular processes, particularly metabolic pathways. Malonylation of STAT6 was confirmed via the use of a specific chemical probe. Notably, we established that malonylation at the lysine 374 site of STAT6 results in increased TCF1 expression, due to alleviated transcriptional repression of TCF1 by STAT6. Collectively, our findings provide compelling evidence that protein malonylation plays a significant role in regulating CD8⁺ T cell memory formation.