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

in Cellular & molecular immunology by Zhihui Cui, Heping Wang, Xiong Feng, Chuyu Wu, Ming Yi, Ruirui He, Ting Pan, Ru Gao, Lingyun Feng, Bo Zeng, Guoling Huang, Yuan Wang, Yanyun Du, Cun-Jin Zhang, Xue Xiao, Chenhui Wang

TLDR

  • The study reveals the critical role of MYO1F in T-cell activation and metabolism regulation, and its implications for immune response and disease.
  • The findings suggest that targeting MYO1F and GAPDH acetylation could be a promising therapeutic strategy for PTCL.
  • The study provides new insights into the mechanisms of T-cell metabolism regulation and its impact on immune response and disease.

Abstract

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.

Overview

  • The study explores the role of MYO1F in T-cell activation and its impact on metabolic regulation and immune response.
  • The researchers found that MYO1F is required for T-cell activation after TCR stimulation and that its absence leads to impaired T-cell activation and increased tumor burden.
  • The study also shows that a fusion protein of VAV1-MYO1F promotes hyperacetylation of GAPDH, leading to aberrant glycolysis and T-cell proliferation.

Comparative Analysis & Findings

  • The study compared the effects of MYO1F knockout on T-cell activation and its impact on tumor burden and autoimmune disease severity.
  • The results show that T-cell-specific Myo1f knockout mice exhibit increased tumor burden and attenuated EAE severity due to impaired T-cell activation.
  • The study also compared the effects of VAV1-MYO1F fusion protein on T-cell metabolism and found that it promotes hyperacetylation of GAPDH and aberrant glycolysis.

Implications and Future Directions

  • The study provides new insights into the mechanisms of T-cell metabolism regulation and its impact on immune response and disease.
  • The findings suggest that targeting MYO1F and GAPDH acetylation could be a promising therapeutic strategy for peripheral T-cell lymphoma (PTCL).
  • Future studies could focus on exploring other potential therapeutic targets and developing novel treatments for PTCL.
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