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Why is the EGO complex required for recovery of budding
yeast cells from rapamycin treatment?
Stephanie K. Evans and Joseph V. Gray
University of Glasgow, Glasgow, UK
Rapamycin is an allosteric inhibitor of TORC1 complexes but
can vary in its effectiveness ranging from apparently complete
inhibition of budding yeast TORC1 to modest inhibition of
mTORC1.
Wild-type yeast cells can resume normal proliferation upon
washout of rapamycin. In contrast, mutants lacking known
activators of TORC1, e.g., components and activators of the EGO
complex, fail to recover from treatment with high concentrations
of rapamycin: the ego- phenotype (Dubouloz et al. 2005; Binda
et al. 2009). It is possible that these non-essential activators are
selectively required to reactivate already inactive TORC1. Our
data indicate that this is not the case.
We find that ego- mutants recover normally from other treatments
that inhibit TORC1. We also find that ego- mutants can recover
from rapamycin treatment but that their time to recovery is
concentration dependent and is much longer than for wild-type
cells treated with the same concentration of the drug. The
ego- phenotype is apparently due to a quantitative defect in
metabolizing rapamycin.
Why should activators of TORC1 be needed for efficient
metabolism of a zenobiotic that inhibits the complex? Our data
suggest that rapamycin does not fully inhibit yeast TORC1 and
that the EGO complex is required for its rapamycin-independent
activity. Thus ego- mutants enter a deeper state of G0 than do
wild-type cells when treated with rapamycin and that this deeper
arrest state results in slower drug metabolism.