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The p97-UBXN1 complex regulates aggresome formation.

Sirisha Mukkavalli1, Jacob Aaron Klickstein1, Betty Ortiz1

  • 1Department of Developmental Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111, USA.

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|March 13, 2021
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The AAA-ATPase p97 (also known as VCP) and its adaptor UBXN1 are crucial for clearing misfolded protein aggregates. Loss of this p97-UBXN1 complex increases protein inclusions linked to neurodegenerative diseases.

Keywords:
AggregateAggresomeInclusion bodyPolyQProteasomeUbiquitin

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Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Neuroscience

Background:

  • Cellular homeostasis relies on the efficient disposal of misfolded proteins.
  • Dysfunctional protein degradation pathways contribute to proteinopathies, a class of protein aggregation disorders.
  • The AAA-ATPase p97 (VCP) and its adaptors target ubiquitylated proteins for degradation via proteasome or autophagy.

Purpose of the Study:

  • To investigate the role of p97 and its adaptors in aggresome formation and clearance.
  • To identify novel roles for p97 adaptors in protein aggregate disposal.
  • To elucidate the molecular mechanisms underlying p97-mediated proteinopathies.

Main Methods:

  • Systematic investigation of p97 and adaptor roles in aggresome formation.
  • Cellular assays to assess aggresome formation and clearance.
  • Knockout studies (UBXN1) and analysis of protein aggregate models (Huntingtin polyQ).

Main Results:

  • p97 (VCP) is demonstrated to mediate both the formation and clearance of aggresomes.
  • A novel role for the adaptor UBXN1 in aggresome formation is identified; UBXN1 is recruited to aggresomes.
  • UBXN1-knockout cells exhibit impaired aggresome formation.
  • Loss of the p97-UBXN1 complex leads to increased Huntingtin polyQ inclusion bodies in mammalian cells and C. elegans.

Conclusions:

  • p97-UBXN1 plays a critical, evolutionarily conserved role in the disposal of protein aggregates.
  • Defects in the p97-UBXN1 pathway contribute to the pathogenesis of proteinopathies, including Huntington's disease.
  • Targeting the p97-UBXN1 pathway may offer therapeutic strategies for protein aggregation disorders.