MYO1F regulates T-cell activation and glycolytic metabolism by promoting the acetylation of GAPDH.

Proper cellular metabolism in T cells is critical for a productive immune response. However, when dysregulated by intrinsic or extrinsic metabolic factors, T cells may contribute to a wide spectrum of diseases, such as cancers and autoimmune diseases. However, the metabolic regulation of T cells remains incompletely understood. Here, we show that MYO1F is required for human and mouse T-cell activation after TCR stimulation and that T-cell-specific Myo1f knockout mice exhibit an increased tumor burden and attenuated EAE severity due to impaired T-cell activation in vivo. Mechanistically, after TCR stimulation, MYO1F is phosphorylated by LCK at tyrosines 607 and 634, which is critical for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) acetylation at Lys84, 86 and 227 mediated by α-TAT1, which is an acetyltransferase, and these processes are important for its activation, cellular glycolysis and thus the effector function of T cells. Importantly, we show that a fusion protein of VAV1-MYO1F, a recurrent peripheral T-cell lymphoma (PTCL)-associated oncogenic protein, promotes hyperacetylation of GAPDH and its activation, which leads to aberrant glycolysis and T-cell proliferation, and that inhibition of the activity of GAPDH significantly limits T-cell activation and proliferation and extends the survival of hVAV1-MYO1F knock-in mice. Moreover, hyperacetylation of GAPDH was confirmed in human PTCL patient samples containing the VAV1-MYO1F gene fusion. Overall, this study revealed not only the mechanisms by which MYO1F regulates T-cell metabolism and VAV1-MYO1F fusion-induced PTCL but also promising therapeutic targets for the treatment of PTCL.