TNFAIP3 promotes survival of CD4 T cells by restricting MTOR and promoting autophagy

Yu Matsuzawa, Shigeru Oshima, Masahiro Takahara, Chiaki Maeyashiki, Yasuhiro Nemoto, Masanori Kobayashi, Yoichi Nibe, Kengo Nozaki, Takashi Nagaishi, Ryuichi Okamoto, Kiichiro Tsuchiya, Tetsuya Nakamura, Averil Ma, Mamoru Watanabe

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47 Citations (Scopus)

Abstract

Autophagy plays important roles in metabolism, differentiation, and survival in T cells. TNFAIP3/A20 is a ubiquitinediting enzyme that is thought to be a negative regulator of autophagy in cell lines. However, the role of TNFAIP3 in autophagy remains unclear. To determine whether TNFAIP3 regulates autophagy in CD4 T cells, we first analyzed Tnfaip3-deficient naïıve CD4 T cells in vitro. We demonstrated that Tnfaip3-deficient CD4 T cells exhibited reduced MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) puncta formation, increased mitochondrial content, and exaggerated reactive oxygen species (ROS) production. These results indicate that TNFAIP3 promotes autophagy after T cell receptor (TCR) stimulation in CD4 T cells. We then investigated the mechanism by which TNFAIP3 promotes autophagy signaling. We found that TNFAIP3 bound to the MTOR (mechanistic target of rapamycin) complex and that Tnfaip3-deficient cells displayed enhanced ubiquitination of the MTOR complex and MTOR activity. To confirm the effects of enhanced MTOR activity in Tnfaip3-deficient cells, we analyzed cell survival following treatment with Torin1, an MTOR inhibitor. Tnfaip3-deficient CD4 T cells exhibited fewer cell numbers than the control cells in vitro and in vivo. In addition, the impaired survival of Tnfaip3-deficient cells was ameliorated with Torin1 treatment in vitro and in vivo. The effect of Torin1 was abolished by Atg5 deficiency. Thus, enhanced MTOR activity regulates the survival of Tnfaip3-deficient CD4 T cells. Taken together, our findings illustrate that TNFAIP3 restricts MTOR signaling and promotes autophagy, providing new insight into the manner in which MTOR and autophagy regulate survival in CD4 T cells.

Original languageEnglish
Pages (from-to)1052-1062
Number of pages11
JournalAutophagy
Volume11
Issue number7
DOIs
Publication statusPublished - Jan 1 2015

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Keywords

  • ATG5
  • Autophagy
  • CD4
  • MTOR
  • TNFAIP3
  • Ubiquitin

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Matsuzawa, Y., Oshima, S., Takahara, M., Maeyashiki, C., Nemoto, Y., Kobayashi, M., Nibe, Y., Nozaki, K., Nagaishi, T., Okamoto, R., Tsuchiya, K., Nakamura, T., Ma, A., & Watanabe, M. (2015). TNFAIP3 promotes survival of CD4 T cells by restricting MTOR and promoting autophagy. Autophagy, 11(7), 1052-1062. https://doi.org/10.1080/15548627.2015.1055439