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Related Experiment Videos

Endocytosis: the DUB version.

Michael J Clague1, Sylvie Urbé

  • 1Physiological laboratory, School of Biomedical Sciences, Crown Street, Liverpool, L69 3BX, UK. clague@liv.ac.uk <clague@liv.ac.uk>

Trends in Cell Biology
|September 26, 2006
PubMed
Summary
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Two deubiquitinating enzymes, AMSH and UBPY, have opposite effects on epidermal growth factor receptor (EGFR) downregulation. AMSH may prevent lysosomal degradation by removing K63-linked ubiquitin chains, while UBPY is crucial for downregulation by acting on both K63 and K48 chains.

Area of Science:

  • Cell biology
  • Molecular biology
  • Biochemistry

Background:

  • Ubiquitination dynamically regulates endosomal cargo protein sorting into multivesicular bodies.
  • Endosomal Sorting Complexes Required for Transport (ESCRT) machinery mediates this process.
  • Deubiquitinating enzymes (DUBs) play critical roles in modulating ubiquitination.
  • Epidermal growth factor receptor (EGFR) is a key cargo protein regulated by this pathway.

Purpose of the Study:

  • To investigate the opposing roles of deubiquitinating enzymes AMSH and UBPY in EGFR downregulation.
  • To elucidate the specific ubiquitin chain linkages targeted by AMSH and UBPY.
  • To understand the contribution of these DUBs to ESCRT complex function and cargo sorting.

Main Methods:

Related Experiment Videos

  • Co-immunoprecipitation assays to study protein interactions.
  • Western blotting to analyze ubiquitination status and protein levels.
  • Downregulation assays to measure EGFR degradation rates.
  • Site-directed mutagenesis to probe enzyme specificities.

    • Main Results:

    • AMSH and UBPY interact with ESCRT components and exhibit opposing effects on EGFR downregulation.
    • AMSH activity is proposed to rescue ubiquitinated cargo by removing K63-linked polyubiquitin chains.
    • UBPY is essential for efficient EGFR downregulation, acting on both K63- and K48-linked polyubiquitin chains.
    • UBPY also regulates the stability of ESCRT-associated proteins like STAM through deubiquitination.

    Conclusions:

    • AMSH and UBPY differentially regulate endosomal cargo sorting and degradation via distinct deubiquitination activities.
    • UBPY's multifaceted role, including targeting K48-linked chains and stabilizing ESCRT components, is critical for receptor downregulation.
    • Understanding these DUBs' specificities provides insights into the complex regulation of receptor trafficking and degradation.