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Updated: Jan 29, 2026
Growth Assays to Assess Polyglutamine Toxicity in Yeast
Published on: March 5, 2012
Sfp1 links TORC1 and cell growth regulation to the yeast SAGA-complex component Tra1 in response to polyQ
Yuwei Jiang1, Matthew D Berg2, Julie Genereaux1,2
1Department of Anatomy and Cell Biology, The University of Western Ontario, London, Ontario, Canada.
Abstract:
Chromatin remodeling regulates gene expression in response to the accumulation of misfolded polyQ proteins associated with Huntington's disease (HD). Tra1 is an essential component of both the SAGA/SLIK and NuA4 transcription co-activator complexes and is linked to multiple cellular processes, including protein trafficking and signaling pathways associated with misfolded protein stress. Cells with compromised Tra1 activity display phenotypes distinct from deletions encoding components of the SAGA and NuA4 complexes, indicating a potentially unique regulatory role of Tra1 in the cellular response to protein misfolding. Here, we employed a yeast model to define how the expression of toxic polyQ expansion proteins affects Tra1 expression and function. Expression of expanded polyQ proteins mimics deletion of SAGA/NuA4 components and results in growth defects under stress conditions. Moreover, deleting genes encoding SAGA and, to a lesser extent, NuA4 components exacerbates polyQ toxicity. Also, cells carrying a mutant Tra1 allele displayed increased sensitivity to polyQ toxicity. Interestingly, expression of polyQ proteins upregulated the expression of TRA1 and other genes encoding SAGA components, revealing a feedback mechanism aimed at maintaining Tra1 and SAGA functional integrity. Moreover, deleting the TORC1 (Target of Rapamycin) effector SFP1 abolished upregulation of TRA1 upon expression of polyQ proteins. While Sfp1 is known to adjust ribosome biogenesis and cell size in response to stress, we identified a new role for Sfp1 in the control of TRA1 expression, linking TORC1 and cell growth regulation to the SAGA acetyltransferase complex during misfolded protein stress.
Insights
Toxic polyQ proteins in Huntington's disease disrupt chromatin remodeling. This study reveals Tra1 and SAGA complex feedback regulation, controlled by TORC1 signaling, to mitigate misfolded protein stress.
Area of Science:
- Molecular Biology
- Genetics
- Cell Biology
Background:
- Chromatin remodeling is crucial for gene expression, especially under cellular stress from misfolded proteins like those in Huntington's disease (HD).
- Tra1, a component of SAGA/SLIK and NuA4 transcription complexes, is involved in protein trafficking and stress response pathways.
- Compromised Tra1 function leads to distinct cellular phenotypes, suggesting a unique role in managing misfolded protein stress.
Purpose of the Study:
- To investigate how toxic polyQ protein expression impacts Tra1 expression and function in a yeast model.
- To elucidate the relationship between polyQ toxicity, Tra1, and the SAGA/NuA4 complexes.
- To identify regulatory mechanisms controlling Tra1 expression during misfolded protein stress.
Main Methods:
- Utilized a yeast model expressing toxic polyQ expansion proteins.
- Assessed growth defects and gene expression changes under stress conditions.
- Investigated the role of Tra1 alleles and the TORC1 pathway effector SFP1.
Main Results:
- Expression of toxic polyQ proteins induced growth defects and mimicked SAGA/NuA4 component deletions.
- Deletion of SAGA/NuA4 genes exacerbated polyQ toxicity; mutant Tra1 alleles increased sensitivity.
- PolyQ protein expression upregulated TRA1 and SAGA component genes, indicating a feedback loop.
- Deleting SFP1 abolished TRA1 upregulation, revealing Sfp1's role in this feedback.
Conclusions:
- Tra1 and SAGA complexes play a significant role in mitigating polyQ toxicity.
- A feedback mechanism involving TRA1 upregulation helps maintain SAGA integrity under stress.
- The TORC1 pathway, via Sfp1, regulates TRA1 expression, connecting cell growth control to the SAGA complex during misfolded protein stress.
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