TORC1 of fission yeast is rapamycin-sensitive

Genes Cells. 2012 Aug;17(8):698-708. doi: 10.1111/j.1365-2443.2012.01618.x. Epub 2012 Jul 5.

Abstract

The target of rapamycin (TOR) protein kinase plays central roles in the regulation of cell growth in response to nutritional availability. TOR forms two distinct multiprotein complexes termed TOR complex 1 (TORC1) and TORC2. Typically, only the activity of TORC1 is inhibited by the immunosuppressant rapamycin. Although rapamycin strongly inhibits cell growth of the budding yeast Saccharomyces cerevisiae through inhibition of TORC1, growth of the fission yeast Schizosaccharomyces pombe appears to be resistant to rapamycin. Here, we demonstrate that rapamycin inhibits the kinase activity of S. pombe TORC1 in vitro in a similar manner to TORC1 of other organisms. We furthermore show that incomplete inhibition of TORC1 by rapamycin underlies the apparent rapamycin resistance of S. pombe. In the presence of caffeine, which potentially lowers TORC1 activity, the growth of wild-type S. pombe cells is sensitive to rapamycin in a TORC1-dependent manner. Moreover, treatment of S. pombe cells with rapamycin plus caffeine induces starvation-specific gene expression and autophagy, similarly to cells with reduced TORC1 activity. These results indicate that rapamycin does inhibit TORC1 in S. pombe, but the inhibition is not sufficient to cause a growth defect. These findings establish a universal action of rapamycin on TORC1 inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caffeine / pharmacology
  • Drug Resistance, Fungal*
  • Enzyme Activation
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Fungal
  • Gene Silencing
  • Genes, Fungal
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Nitrogen / metabolism
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Schizosaccharomyces / drug effects*
  • Schizosaccharomyces / enzymology
  • Schizosaccharomyces / genetics
  • Schizosaccharomyces / growth & development
  • Schizosaccharomyces pombe Proteins / genetics
  • Schizosaccharomyces pombe Proteins / metabolism*
  • Serial Passage
  • Sirolimus / pharmacology*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Multiprotein Complexes
  • Schizosaccharomyces pombe Proteins
  • Transcription Factors
  • Caffeine
  • Phosphatidylinositol 3-Kinases
  • TOR Serine-Threonine Kinases
  • tor2 protein, S pombe
  • Nitrogen
  • Sirolimus