Isp7 Is a Novel Regulator of Amino Acid Uptake in the TOR Signaling Pathway

Abstract

TOR proteins reside in two distinct complexes, TOR complexes 1 and 2 (TORC1 and TORC2), that are central for the regulation of cellular growth, proliferation, and survival. TOR is also the target for the immunosuppressive and anticancer drug rapamycin. In Schizosaccharomyces pombe, disruption of the TSC complex, mutations in which can lead to the tuberous sclerosis syndrome in humans, results in a rapamycin-sensitive phenotype under poor nitrogen conditions. We show here that the sensitivity to rapamycin is mediated via inhibition of TORC1 and suppressed by overexpression of isp7⁺, a member of the family of 2-oxoglutarate-Fe(II)-dependent oxygenase genes. The transcript level of isp7⁺ is negatively regulated by TORC1 but positively regulated by TORC2. Yet we find extensive similarity between the transcriptome of cells disrupted for isp7⁺ and cells mutated in the catalytic subunit of TORC1. Moreover, Isp7 regulates amino acid permease expression in a fashion similar to that of TORC1 and opposite that of TORC2. Overexpression of isp7⁺ induces TORC1-dependent phosphorylation of ribosomal protein Rps6 while inhibiting TORC2-dependent phosphorylation and activation of the AGC-like kinase Gad8. Taken together, our findings suggest a central role for Isp7 in amino acid homeostasis and the presence of isp7⁺-dependent regulatory loops that affect both TORC1 and TORC2.

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Isp7 Is a Novel Regulator of Amino Acid Uptake in the TOR Signaling Pathway

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01473-13.

ACKNOWLEDGMENTS

We thank C. Gancedo, N. Jones, S. Moreno, K. Shiozaki, M. van Slegtenhorst, F. Tamanoi, M. Yamamoto, and M. Yanagida for strains and plasmids and members of the Kupiec laboratory for encouragement and support.

This research was supported by grants from the Association for International Research (AICR) (11-0281) and by grants from the Open University of Israel Research fund (grant no. 37076).