Hyperactive TORC1 sensitizes yeast cells to endoplasmic reticulum stress by compromising cell wall integrity

FEBS Lett. 2019 Aug;593(15):1957-1973. doi: 10.1002/1873-3468.13463. Epub 2019 Jun 12.

Abstract

Accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR). Here, we investigated how the target of rapamycin complex 1 (TORC1) signaling cascade acts in parallel with the UPR to regulate ER stress sensitivity. Using Saccharomyces cerevisiae, we found that TORC1 signaling is attenuated during ER stress and constitutive activation of TORC1 increases sensitivity to ER stressors independently of the UPR. Transcriptome analysis revealed that TORC1 hyperactivation results in cell wall remodelling. Conversely, hyperactive TORC1 sensitizes cells to cell wall stressors, including the antifungal caspofungin. Elucidating the crosstalk between the UPR, cell wall integrity, and TORC1 signaling may uncover new paradigms through which the response to protein misfolding is regulated.

Keywords: TORC1; caspofungin; cell wall integrity; endoplasmic reticulum stress; unfolded protein response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caspofungin / pharmacology
  • Cell Wall / metabolism*
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum Stress / drug effects
  • Gene Expression Profiling
  • Gene Expression Regulation, Fungal / drug effects
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / genetics*
  • Saccharomyces cerevisiae Proteins / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Unfolded Protein Response / drug effects

Substances

  • Saccharomyces cerevisiae Proteins
  • TORC1 protein complex, S cerevisiae
  • Transcription Factors
  • Caspofungin