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Heteromeric p97/p97R155C complexes induce dominant negative changes in wild-type and autophagy 9-deficient

Khalid Arhzaouy1, Karl-Heinz Strucksberg, Sze Man Tung

  • 1Intitute for Biochemistry I, Medical Faculty, University of Cologne, Cologne, Germany.

Plos One
|October 12, 2012
PubMed

Insights

Mutant VCP (p97) protein causes cellular dysfunction, but its expression in ATG9-deficient cells rescues these defects. This suggests a novel mutual inhibition mechanism between VCP (p97) and ATG9 in essential cellular processes.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • Heterozygous VCP (p97) gene mutations lead to IBMPFD, ALS14, and HSP.
  • The R155C mutation is the most common VCP (p97) mutation.
  • Understanding VCP (p97) function is crucial for neurodegenerative disease research.

Purpose of the Study:

  • Investigate the function of wild-type and mutant VCP (p97) in Dictyostelium discoideum.
  • Examine the interaction between VCP (p97) and autophagy protein ATG9.
  • Elucidate the cellular consequences of VCP (p97) mutations.

Main Methods:

  • Generated Dictyostelium discoideum strains expressing wild-type or mutant VCP (p97)-RFP.
  • Utilized native gel electrophoresis and co-immunoprecipitation to study protein assembly and interactions.
  • Assessed cellular phenotypes including growth, phototaxis, development, proteasomal activity, and protein aggregation.

Main Results:

  • Both wild-type and mutant VCP (p97) form hexamers and heteromers with endogenous p97.
  • Mutant VCP (p97) expression altered cell growth, development, proteasomal activity, and led to increased protein aggregates.
  • Expression of mutant VCP (p97)-RFP in ATG9-deficient cells partially or fully rescued the observed phenotypes.

Conclusions:

  • VCP (p97) mutations disrupt multiple essential cellular processes.
  • A novel mode of VCP (p97) and ATG9 interaction, involving mutual inhibition, is proposed.
  • VCP (p97) plays a critical role in cellular homeostasis, and its dysfunction contributes to disease pathogenesis.

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