한빛사논문
- 조회354
Yeon Jun Kang 1,2, Woorim Song 1,2, Su Jeong Lee 1,2, Seung Ah Choi 1,2, Sihyun Chae 3,4, Bo Ruem Yoon 2, Hee Young Kim 2, Jung Ho Lee 3, Chulwoo Kim 5, Joo-Youn Cho 3,4, Hyun Je Kim 2,3 and Won-Woo Lee 1,2,6,*
1Laboratory of Autoimmunity and Inflammation (LAI), Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
2Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
3Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 03080, Korea.
4Department of Clinical Pharmacology and Therapeutics, Seoul National University, College of Medicine and Hospital, Seoul 03080, Republic of Korea.
5Department of Microbiology, Institute for Viral Diseases, Korea University College of Medicine, Seoul 02841, Republic of Korea.
6Seoul National University Cancer Research Institute, Institue of Endemic Diseases and Ischemic/Hypoxic Disease Institute, Seoul National University Medical Research Center, Seoul National University Hospital Biomedical Research Institute, Seoul 03080, Republic of Korea.
*Corresponding author: correspondence to Won-Woo Lee
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 (HPDL). Inhibition of BCAT1-mediated cytosolic leucine metabolism, either with BCAT1 inhibitor 2 (Bi2) or through BCAT1, HPD, or HPDL silencing using shRNA, attenuates IL-17 production, whereas HMB supplementation abrogates this effect. Mechanistically, HMB contributes to the regulation of the mTORC1-HIF1α pathway, a major signaling pathway for IL-17 production, by increasing the mRNA expression of HIF1α. This finding was corroborated by the observation that treatment with L-β-homoleucine (LβhL), a leucine analog and competitive inhibitor of BCAT1, decreased IL-17 production by TCR-activated CD4+ T cells. In an in vivo experimental autoimmune encephalomyelitis (EAE) model, blockade of BCAT1-mediated leucine catabolism, either through a BCAT1 inhibitor or LβhL treatment, mitigated EAE severity by decreasing HIF1α expression and IL-17 production in spinal cord mononuclear cells. Our findings elucidate the role of BCAT1-mediated cytoplasmic leucine catabolism in modulating IL-17 production via HMB-mediated regulation of mTORC1-HIF1α, providing insights into its relevance to inflammatory conditions.
논문정보
- Research article
- 2024년 08월 (BRIC 등록일 2024-08-02)
- 국내 연구진
- 의약학 > 면역의학
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