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TORC1 regulates autophagy induction in response to proteotoxic stress in yeast and human cells

Kazuki Suda1, Atsuki Kaneko2, Mitsugu Shimobayashi3

  • 1Department of Biological Science, Shizuoka University, Shizuoka, 422-8021, Japan.

Biochemical and Biophysical Research Communications
|February 25, 2019
PubMed

Insights

Proteotoxic stress triggers autophagy, a cellular cleanup process, by inhibiting the TORC1 pathway. This conserved mechanism helps eukaryotic cells manage misfolded proteins.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Protein homeostasis is crucial for cell survival, with misfolded and aggregated proteins posing a significant threat.
  • Autophagy is a key cellular pathway responsible for degrading protein aggregates.
  • The precise mechanisms by which proteotoxic stress induces autophagy remain largely unknown.

Purpose of the Study:

  • To investigate how proteotoxic stress induces autophagy.
  • To identify the molecular players involved in this stress response.
  • To determine if this mechanism is conserved across different eukaryotic species.

Main Methods:

  • Treatment of budding yeast with azetidine-2-carboxylic acid (AZC), a toxic proline analog, to induce proteotoxic stress.
  • Analysis of target of rapamycin complex 1 (TORC1) and target of rapamycin complex 2 (TORC2) activity.
  • Assessment of autophagy induction and Atg13 phosphorylation.
  • Comparative studies in fission yeast and human cells.

Main Results:

  • Proteotoxic stress induced by AZC treatment activated autophagy in budding yeast.
  • AZC treatment led to the inhibition of TORC1 activity and dephosphorylation of Atg13, a critical autophagy regulator.
  • TORC2 activity remained unaffected by AZC treatment.
  • Similar TORC1 inactivation and autophagy induction were observed in fission yeast and human cells.

Conclusions:

  • The target of rapamycin complex 1 (TORC1) pathway is a conserved key regulator in eukaryotic cells' response to proteotoxic stress.
  • Inhibition of TORC1 is a critical step linking proteotoxic stress to autophagy induction.
  • This study provides significant insights into the molecular mechanisms underlying cellular adaptation to proteotoxic stress.
Keywords:
AutophagyAzetidine-2-carboxylic acid (AZC)Proteotoxic stressTarget of rapamycin complex 1 (TORC1)

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