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Divergent regulation of α-arrestin ARRDC3 function by ubiquitination

Helen Wedegaertner1,2, Oye Bosompra1,2, Irina Kufareva1,3

  • 1Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA92093.

Molecular Biology of the Cell
|May 24, 2023
PubMed

Insights

Ubiquitination regulates the tumor suppressor α-arrestin ARRDC3, controlling its protein trafficking, signaling, and degradation. This posttranslational modification is essential for ARRDC3

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • The α-arrestin ARRDC3 is a tumor suppressor in invasive breast cancer.
  • ARRDC3 acts as an adaptor protein regulating protein trafficking and cellular signaling.
  • The molecular mechanisms governing ARRDC3 function are largely unknown.

Purpose of the Study:

  • To investigate the posttranslational modifications regulating ARRDC3 function.
  • To elucidate the role of ubiquitination in controlling ARRDC3's tumor-suppressive activities.

Main Methods:

  • Investigated ubiquitination of ARRDC3.
  • Identified PPXY motifs in the ARRDC3 C-tail domain.
  • Assessed the impact of ubiquitination and PPXY motifs on ARRDC3 function, localization, and degradation.
  • Examined interaction with WWP2 E3 ubiquitin ligase.

Main Results:

  • Ubiquitination is a key regulator of ARRDC3 function.
  • Two PPXY motifs in the ARRDC3 C-tail mediate ubiquitination.
  • Ubiquitination and PPXY motifs are critical for regulating GPCR trafficking and signaling.
  • Ubiquitination controls ARRDC3 protein degradation and subcellular localization.
  • ARRDC3 interacts with the WWP2 E3 ubiquitin ligase.

Conclusions:

  • Ubiquitination is a crucial posttranslational modification for ARRDC3 function.
  • The PPXY motifs and ubiquitination mediate ARRDC3's role in protein trafficking, signaling, and degradation.
  • This study reveals a novel regulatory mechanism for ARRDC3's diverse functions in cancer.

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