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Regulation of T-cell survival and mitochondrial homeostasis by TSC1.

Publication ,  Journal Article
O'Brien, TF; Gorentla, BK; Xie, D; Srivatsan, S; McLeod, IX; He, Y-W; Zhong, X-P
Published in: Eur J Immunol
November 2011

The mammalian target of rapamycin (mTOR) is a key regulator of cell growth and metabolism. It associates with multiple proteins and forms two distinct signaling complexes, mTORC1 and mTORC2. Accumulating evidence has revealed critical roles for intact mTOR signaling during T-cell activation and responses to microbial infection. However, the importance of mTOR regulation in T cells has yet to be explored. The TSC1/TSC2 complex has been shown to inhibit mTORC1 signaling in cell line models. We show here that deletion of TSC1 in the murine T-cell lineage results in a dramatic reduction of the peripheral T-cell pool, correlating with increased cell death. While mTORC1 is constitutively activated, mTORC2 signaling, reflected by Akt phosphorylation and activity, is decreased in TSC1-deficient T cells. Furthermore, TSC1-deficient T cells contain elevated reactive oxygen species (ROS) and exhibit decreased mitochondrial content and membrane potential, which is correlated with the activation of the intrinsic death pathway. Overall, our results demonstrate that TSC1 differentially regulates mTORC1 and mTORC2 activity, promotes T-cell survival, and is critical for normal mitochondrial homeostasis in T cells.

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Published In

Eur J Immunol

DOI

EISSN

1521-4141

Publication Date

November 2011

Volume

41

Issue

11

Start / End Page

3361 / 3370

Location

Germany

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tuberous Sclerosis Complex 1 Protein
  • Transcription Factors
  • Trans-Activators
  • TOR Serine-Threonine Kinases
  • T-Lymphocytes
  • Signal Transduction
  • Real-Time Polymerase Chain Reaction
  • Proteins
  • Multiprotein Complexes
 

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O’Brien, T. F., Gorentla, B. K., Xie, D., Srivatsan, S., McLeod, I. X., He, Y.-W., & Zhong, X.-P. (2011). Regulation of T-cell survival and mitochondrial homeostasis by TSC1. Eur J Immunol, 41(11), 3361–3370. https://doi.org/10.1002/eji.201141411
O’Brien, Thomas F., Balachandra K. Gorentla, Danli Xie, Sruti Srivatsan, Ian X. McLeod, You-Wen He, and Xiao-Ping Zhong. “Regulation of T-cell survival and mitochondrial homeostasis by TSC1.Eur J Immunol 41, no. 11 (November 2011): 3361–70. https://doi.org/10.1002/eji.201141411.
O’Brien TF, Gorentla BK, Xie D, Srivatsan S, McLeod IX, He Y-W, et al. Regulation of T-cell survival and mitochondrial homeostasis by TSC1. Eur J Immunol. 2011 Nov;41(11):3361–70.
O’Brien, Thomas F., et al. “Regulation of T-cell survival and mitochondrial homeostasis by TSC1.Eur J Immunol, vol. 41, no. 11, Nov. 2011, pp. 3361–70. Pubmed, doi:10.1002/eji.201141411.
O’Brien TF, Gorentla BK, Xie D, Srivatsan S, McLeod IX, He Y-W, Zhong X-P. Regulation of T-cell survival and mitochondrial homeostasis by TSC1. Eur J Immunol. 2011 Nov;41(11):3361–3370.
Journal cover image

Published In

Eur J Immunol

DOI

EISSN

1521-4141

Publication Date

November 2011

Volume

41

Issue

11

Start / End Page

3361 / 3370

Location

Germany

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tuberous Sclerosis Complex 1 Protein
  • Transcription Factors
  • Trans-Activators
  • TOR Serine-Threonine Kinases
  • T-Lymphocytes
  • Signal Transduction
  • Real-Time Polymerase Chain Reaction
  • Proteins
  • Multiprotein Complexes