Impairment of the ubiquitin-proteasome system by protein aggregation

Science. 2001 May 25;292(5521):1552-5. doi: 10.1126/science.292.5521.1552.

Abstract

Intracellular deposition of aggregated and ubiquitylated proteins is a prominent cytopathological feature of most neurodegenerative disorders. Whether protein aggregates themselves are pathogenic or are the consequence of an underlying molecular lesion is unclear. Here, we report that protein aggregation directly impaired the function of the ubiquitin-proteasome system. Transient expression of two unrelated aggregation-prone proteins, a huntingtin fragment containing a pathogenic polyglutamine repeat and a folding mutant of cystic fibrosis transmembrane conductance regulator, caused nearly complete inhibition of the ubiquitin-proteasome system. Because of the central role of ubiquitin-dependent proteolysis in regulating fundamental cellular events such as cell division and apoptosis, our data suggest a potential mechanism linking protein aggregation to cellular disregulation and cell death.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acetylcysteine / analogs & derivatives*
  • Acetylcysteine / pharmacology
  • Amino Acid Sequence
  • Cell Death
  • Cell Line
  • Cysteine Endopeptidases / metabolism*
  • Cysteine Proteinase Inhibitors / pharmacology
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
  • Endoplasmic Reticulum / metabolism
  • G2 Phase
  • Green Fluorescent Proteins
  • Humans
  • Huntingtin Protein
  • Inclusion Bodies / metabolism
  • Leupeptins / pharmacology
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Molecular Sequence Data
  • Multienzyme Complexes / antagonists & inhibitors
  • Multienzyme Complexes / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Proteasome Endopeptidase Complex
  • Recombinant Fusion Proteins / metabolism
  • Transfection
  • Ubiquitins / metabolism*

Substances

  • CFTR protein, human
  • Cysteine Proteinase Inhibitors
  • HTT protein, human
  • Huntingtin Protein
  • Leupeptins
  • Luminescent Proteins
  • Multienzyme Complexes
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Recombinant Fusion Proteins
  • Ubiquitins
  • acetylleucyl-leucyl-norleucinal
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • lactacystin
  • Green Fluorescent Proteins
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex
  • Acetylcysteine