Tetraspanin CD63 promotes targeting and lysosomal proteolysis of membrane-type 1 matrix metalloproteinase

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Takahisa Takino1, Hisashi Miyamori, Noriko Kawaguchi

  • 1Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, 920-0934, Kanazawa, Japan.

Biochemical and Biophysical Research Communications
|April 23, 2003
PubMed

Insights

Internalized membrane-type 1 matrix metalloproteinase (MT1-MMP) is degraded in lysosomes. CD63 protein facilitates this process by targeting MT1-MMP for lysosomal proteolysis, revealing a novel regulatory pathway.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Membrane-type 1 matrix metalloproteinase (MT1-MMP) undergoes internalization from the cell surface.
  • The degradation pathway and ultimate fate of internalized MT1-MMP remain largely uncharacterized.

Purpose of the Study:

  • To elucidate the degradation mechanism of internalized MT1-MMP.
  • To investigate the role of CD63 in the cellular trafficking and degradation of MT1-MMP.

Main Methods:

  • Treatment with lysosomal protease inhibitor (chloroquine).
  • Ectopic expression of CD63 and its mutants.
  • Co-immunoprecipitation to assess protein complex formation.
  • Analysis of MT1-MMP localization in CD63-positive lysosomes.

Main Results:

  • Chloroquine treatment inhibited MT1-MMP degradation and caused its accumulation in CD63-positive lysosomes.
  • Ectopic CD63 expression accelerated MT1-MMP degradation, an effect blocked by chloroquine.
  • MT1-MMP and CD63 form a complex via MT1-MMP's hemopexin-like domain and CD63's N-terminal region.
  • A CD63 mutant lacking a lysosomal targeting motif failed to enhance MT1-MMP degradation.

Conclusions:

  • Internalized MT1-MMP is targeted for lysosomal degradation.
  • CD63 plays a crucial role in regulating MT1-MMP levels by mediating its lysosomal targeting and proteolysis.
  • The interaction between MT1-MMP and CD63 is essential for this degradation pathway.

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