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The sheddase activity of ADAM17/TACE is regulated by the tetraspanin CD9

Maria Dolores Gutiérrez-López1, Alvaro Gilsanz, María Yáñez-Mó

  • 1Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Nicolás Cabrera 1, Campus de Cantoblanco, 28049 Madrid, Spain.

Cellular and Molecular Life Sciences : CMLS
|March 3, 2011
PubMed

Insights

The tetraspanin CD9 protein directly binds to ADAM17 (a disintegrin and metalloproteinase 17), a key enzyme in inflammation. This interaction inhibits ADAM17

Area of Science:

  • Biochemistry
  • Cell Biology
  • Immunology

Background:

  • ADAM17 (a disintegrin and metalloproteinase 17), also known as TACE, is crucial for shedding cell surface proteins, including the pro-inflammatory cytokine TNF-α.
  • The regulatory mechanisms governing ADAM17's metalloproteinase activity are not well understood.
  • ADAM17 plays significant roles in cellular processes like development, adhesion, migration, differentiation, and proliferation.

Purpose of the Study:

  • To investigate the regulatory mechanisms of ADAM17 metalloproteinase activity.
  • To determine the relationship between the tetraspanin CD9 and ADAM17.
  • To elucidate the functional consequences of CD9-ADAM17 interaction on ADAM17 activity.

Main Methods:

  • Co-localization studies on endothelial and monocytic cells.
  • In situ proximity ligation assays.
  • Co-immunoprecipitation, crosslinking, and pull-down experiments.
  • Functional assays assessing ADAM17 sheddase activity upon CD9 modulation (antibody treatment, neoexpression, silencing).

Main Results:

  • ADAM17 and CD9 were found to partially co-localize on the cell surface.
  • Direct physical association between CD9 and ADAM17 was confirmed through multiple biochemical methods.
  • CD9 engagement (antibody treatment) or increased expression suppressed ADAM17 sheddase activity.
  • Silencing CD9 led to enhanced ADAM17 activity against substrates like TNF-α and ICAM-1.

Conclusions:

  • CD9 directly associates with ADAM17.
  • CD9 acts as a negative regulator of ADAM17's sheddase activity.
  • This interaction provides a novel mechanism for controlling ADAM17-mediated protein shedding and inflammatory responses.

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