The tumor suppressor menin prevents effector CD8 T-cell dysfunction by targeting mTORC1-dependent metabolic activation

Junpei Suzuki, Takeshi Yamada, Kazuki Inoue, Shogo Nabe, Makoto Kuwahara, Nobuaki Takemori, Ayako Takemori, Seiji Matsuda, Makoto Kanoh, Yuuki Imai, Masaki Yasukawa and Masakatsu Yamashita ()
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Junpei Suzuki: Ehime University, Shitsukawa
Takeshi Yamada: Ehime University, Shitsukawa
Kazuki Inoue: Ehime University
Shogo Nabe: Ehime University, Shitsukawa
Makoto Kuwahara: Ehime University, Shitsukawa
Nobuaki Takemori: Ehime University
Ayako Takemori: Ehime University
Seiji Matsuda: Ehime University, Shitsukawa
Makoto Kanoh: Ehime University, Shitsukawa
Yuuki Imai: Ehime University
Masaki Yasukawa: Ehime University, Shitsukawa
Masakatsu Yamashita: Ehime University, Shitsukawa

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract While menin plays an important role in preventing T-cell dysfunction, such as senescence and exhaustion, the regulatory mechanisms remain unclear. We found that menin prevents the induction of dysfunction in activated CD8 T cells by restricting the cellular metabolism. mTOR complex 1 (mTORC1) signaling, glycolysis, and glutaminolysis are augmented by menin deficiency. Rapamycin treatment prevents CD8 T-cell dysfunction in menin-deficient CD8 T cells. Limited glutamine availability also prevents CD8 T-cell dysfunction induced by menin deficiency, and its inhibitory effect is antagonized by α-ketoglutarate (α-KG), an intermediate metabolite of glutaminolysis. α-KG-dependent histone H3K27 demethylation seems to be involved in the dysfunction in menin-deficient CD8 T cells. We also found that α-KG activates mTORC1-dependent central carbon metabolism. These findings suggest that menin maintains the T-cell functions by limiting mTORC 1 activity and subsequent cellular metabolism.

Date: 2018
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DOI: 10.1038/s41467-018-05854-6

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