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<p>The differentiation of Th17 and iTreg is tightly associated with fatty acid metabolism. TGFβ1-induced iTreg differentiation from Th0 relies on fatty acid oxidation (FAO), whereas IL-6 with TGFβ1 shifts metabolism to Th17-preferred fatty acid synthesis (FAS). However, how IL-6 reprograms fatty acid metabolism remains unclear. Here, we unveiled that TGFβ1-activated JNK is recruited to the <i>Klhl25</i> promoter by NF-YA. JNK then phosphorylates histone H3 at Ser10 to activate <i>Klhl25</i> transcription, leading to the ubiquitination-dependent degradation of ATP-citrate lyase (ACLY) and the switch from FAS to FAO, which supports iTreg generation. Whereas, upon IL-6 signaling, NF-YA is phosphorylated by ERK, losing its DNA binding ability, which shuts off TGFβ1-JNK-mediated <i>Klhl25</i> transcription and ACLY ubiquitination, thereby increasing FAS and supporting Th17 differentiation. This study demonstrated that KLHL25-ACLY module functions as a switch in response to TGFβ1 and IL-6 signals, playing a decisive role in the fate determination of iTreg/Th17 differentiation.</p><p></p>

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KLHL25-ACLY module functions as a switch in the fate determination of the differentiation of iTreg/Th17

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月21日

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  • Miaomiao Tian,
  • Fengqi Hao,
  • Xin Jin,
  • Xinyu Wang,
  • Tianyi Chang,
  • Shuang He,
  • Huiyue Wang,
  • Ying Jiang,
  • Yang Wang,
  • Jia Liu,
  • Yunpeng Feng,
  • Dan Li,
  • Zhinan Yin,
  • Xueqing Ba,
  • Min Wei

摘要

The differentiation of Th17 and iTreg is tightly associated with fatty acid metabolism. TGFβ1-induced iTreg differentiation from Th0 relies on fatty acid oxidation (FAO), whereas IL-6 with TGFβ1 shifts metabolism to Th17-preferred fatty acid synthesis (FAS). However, how IL-6 reprograms fatty acid metabolism remains unclear. Here, we unveiled that TGFβ1-activated JNK is recruited to the Klhl25 promoter by NF-YA. JNK then phosphorylates histone H3 at Ser10 to activate Klhl25 transcription, leading to the ubiquitination-dependent degradation of ATP-citrate lyase (ACLY) and the switch from FAS to FAO, which supports iTreg generation. Whereas, upon IL-6 signaling, NF-YA is phosphorylated by ERK, losing its DNA binding ability, which shuts off TGFβ1-JNK-mediated Klhl25 transcription and ACLY ubiquitination, thereby increasing FAS and supporting Th17 differentiation. This study demonstrated that KLHL25-ACLY module functions as a switch in response to TGFβ1 and IL-6 signals, playing a decisive role in the fate determination of iTreg/Th17 differentiation.