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 ca...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 byα-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.展开更多
基金supported by grants from the National Science Fund for Distinguished Young Scholars(82225029,to C.H.W.)the Youth Fund of the National Natural Science Foundation of China(82302628,to Y.Y.D.,82301989,to R.R.H.,82301987 to B.Z.and 82402704 to Y.Y.L.)+5 种基金the Original Exploration Program of the National Natural Science Foundation of China(82150102,to C.H.W.)the National Key Research and Development Program of China(2020YFA0710700,to C.H.W.)the Postdoctoral Foundation of China(2022M720658,to Y.Y.D.,and 2022M720659 to R.R.H.)the Sichuan Postdoctoral Innovation Plan(BX202202,to Y.Y.D.)the Postdoctoral Foundation of Sichuan Provincial People’s Hospital(2022BH01,to R.R.H.and 2022BH07,to M.Y.)the Postdoctoral Foundation of Sichuan Province(TB2022086,to R.R.H.,TB2023092,to L.Y.F.).
文摘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 byα-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.
