Inactivation of Mammalian Target of Rapamycin Increases STAT1 Nuclear Content and Transcriptional Activity in α4- and Protein Phosphatase 2A-dependent Fashion

• Published in: The Journal of biological chemistry Vol. 284; no. 36; pp. 24341 - 24353
• Main Authors: Fielhaber, Jill A., Han, Ying-Shan, Tan, Jason, Xing, Shuo, Biggs, Catherine M., Joung, Kwang-Bo, Kristof, Arnold S.
• Format: Journal Article
• Language: English
• Published: 9650 Rockville Pike, Bethesda, MD 20814, U.S.A Elsevier Inc 04.09.2009; American Society for Biochemistry and Molecular Biology
• Subjects: Mechanisms of Signal Transduction
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.033530

Target of rapamycin (TOR) is a highly conserved serine/threonine kinase that controls cell growth, primarily via regulation of protein synthesis. In Saccharomyces cerevisiae, TOR can also suppress the transcription of stress response genes by a mechanism involving Tap42, a serine/threonine phosphatase subunit, and the transcription factor Msn2. A physical association between mammalian TOR (mTOR) and the transcription factor signal transducer and activator of transcription-1 (STAT1) was recently identified in human cells, suggesting a similar role for mTOR in the transcription of interferon-γ-stimulated genes. In the current study, we identified a macromolecular protein complex composed of mTOR, STAT1, the Tap42 homologue α4, and the protein phosphatase 2A catalytic subunit (PP2Ac). Inactivation of mTOR enhanced its association with STAT1 and increased STAT1 nuclear content in PP2Ac-dependent fashion. Depletion of α4, PP2A, or mTOR enhanced the induction of early (i.e. IRF-1) and late (i.e. caspase-1, hiNOS, and Fas) STAT1-dependent genes. The regulation of IRF-1 or caspase-1 by mTOR was independent of other known mTOR effectors p70 S6 kinase and Akt. These results describe a new role for mTOR and α4/PP2A in the control of STAT1 nuclear content, and the expression of interferon-γ-sensitive genes involved in immunity and apoptosis.