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Assays for the Degradation of Misfolded Proteins in Cells
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Published on: August 28, 2016

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Nonsense-mediated mRNA decay factor UPF1 promotes aggresome formation

Yeonkyoung Park1,2, Joori Park1,2, Hyun Jung Hwang1,2

  • 1Creative Research Initiatives Center for Molecular Biology of Translation, Korea University, Seoul, 02841, Republic of Korea.

Nature Communications
|June 21, 2020
PubMed

Insights

Nonsense-mediated mRNA decay (NMD) byproducts, truncated polypeptides, accumulate in aggresomes when protein degradation is overwhelmed. UPF1 hyperphosphorylation targets these aggregates for clearance, suppressing stress-induced apoptosis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Nonsense-mediated mRNA decay (NMD) is a crucial mRNA surveillance pathway.
  • NMD can generate truncated, misfolded polypeptides as byproducts.
  • The ubiquitin-proteasome system (UPS) degrades misfolded proteins, but can be overwhelmed.

Purpose of the Study:

  • To investigate the fate of NMD-generated polypeptides when the UPS is overwhelmed.
  • To elucidate the role of UPF1 in the cellular response to proteotoxic stress.
  • To understand the mechanism of aggresome targeting and clearance.

Main Methods:

  • Cellular assays to monitor polypeptide accumulation and degradation.
  • Biochemical analysis of UPF1 phosphorylation and its interaction with cellular machinery.
  • Single-particle tracking to visualize aggregate movement.
  • Apoptosis assays under proteotoxic stress conditions.

Main Results:

  • Misfolded polypeptides, including NMD-polypeptides, accumulate in aggresomes when the UPS is overwhelmed.
  • UPF1 hyperphosphorylation is essential for targeting these aggregates to aggresomes via the CTIF-eEF1A1-DCTN1 complex.
  • UPF1 enhances the efficiency and accuracy of aggregate transport to aggresomes.
  • UPF1 hyperphosphorylation suppresses apoptosis induced by proteotoxic stress.

Conclusions:

  • UPF1 plays a dual role in both mRNA quality control and protein surveillance.
  • Hyperphosphorylated UPF1 acts as a key regulator in the aggresome pathway, managing misfolded protein aggregates.
  • This pathway is critical for cellular survival under proteotoxic stress.

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