Inhibition of BCAT1-mediated cytosolic leucine metabolism regulates Th17 responses via the mTORC1-HIF1α pathway.

ABSTRACT: Branched-chain amino acids (BCAAs), particularly leucine, are indispensable AAs for immune regulation through metabolic rewiring. However, the molecular mechanism underlying this phenomenon remains unclear. Our investigation revealed that T-cell receptor (TCR)-activated human CD4⁺ T cells increase the expression of BCAT1, a cytosolic enzyme responsible for BCAA catabolism, and SLC7A5, a major BCAA transporter. This upregulation facilitates increased leucine influx and catabolism, which are particularly crucial for Th17 responses. Activated CD4⁺ T cells induce an alternative pathway of cytosolic leucine catabolism, generating a pivotal metabolite, β-hydroxy β-methylbutyric acid (HMB), by acting on BCAT1 and 4-hydroxyphenylpyruvate dioxygenase (HPD)/HPD-like protein (HP

SUBMITTER: Kang YJ 

PROVIDER: S-EPMC11372109 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature