2. Academic Validation
  3. ACLY ubiquitination by CUL3-KLHL25 induces the reprogramming of fatty acid metabolism to facilitate iTreg differentiation

ACLY ubiquitination by CUL3-KLHL25 induces the reprogramming of fatty acid metabolism to facilitate iTreg differentiation

  • Elife. 2021 Sep 7;10:e62394. doi: 10.7554/eLife.62394.
Miaomiao Tian # 1,  Fengqi Hao # 1,  Xin Jin 1,  Xue Sun 1,  Ying Jiang 1,  Yang Wang 1,  Dan Li 2 3,  Tianyi Chang 1,  Yingying Zou 1,  Pinghui Peng 1,  Chaoyi Xia 1,  Jia Liu 1,  Yuanxi Li 1,  Ping Wang 4,  Yunpeng Feng 1,  Min Wei 1
Affiliations

Affiliations

  • 1 Key Laboratory of Molecular Epigenetics of the Ministry of Education (MOE), Northeast Normal University, Changchun, China.
  • 2 Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3 Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4 Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.
  • # Contributed equally.
PMID: 34491895 DOI: 10.7554/eLife.62394
Abstract

Inducible regulatory T (iTreg) cells play a central role in immune suppression. As iTreg cells are differentiated from activated T (Th0) cells, cell metabolism undergoes dramatic changes, including a shift from fatty acid synthesis (FAS) to fatty acid oxidation (FAO). Although the reprogramming in fatty acid metabolism is critical, the mechanism regulating this process during iTreg differentiation is still unclear. Here we have revealed that the enzymatic activity of ATP-citrate lyase (ACLY) declined significantly during iTreg differentiation upon transforming growth factor β1 (TGFβ1) stimulation. This reduction was due to CUL3-KLHL25-mediated ACLY ubiquitination and degradation. As a consequence, malonyl-CoA, a metabolic intermediate in FAS that is capable of inhibiting the rate-limiting Enzyme in FAO, carnitine palmitoyltransferase 1 (CPT1), was decreased. Therefore, ACLY ubiquitination and degradation facilitate FAO and thereby iTreg differentiation. Together, we suggest TGFβ1-CUL3-KLHL25-ACLY axis as an important means regulating iTreg differentiation and bring insights into the maintenance of immune homeostasis for the prevention of immune diseases.

Keywords

ATP-citrate lyase; CUL3-KLHL25; E. coli; TGFβ1; human; iTreg; immunology; inflammation; mouse; ubiquitination; virus.

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