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The shedding activity of ADAM17 is sequestered in lipid rafts

Edwige Tellier1, Matthias Canault, Laure Rebsomen

  • 1Inserm, U626, Marseilles, France.

Experimental Cell Research
|October 3, 2006
PubMed

Insights

The tumor necrosis factor-alpha (TNF) converting enzyme (ADAM17) is regulated by its localization within lipid rafts. Cholesterol depletion enhances ADAM17 activity, highlighting the role of membrane microdomains in controlling protein shedding.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Background:

  • ADAM17 (TNF-alpha converting enzyme) cleaves transmembrane proteins, but its regulation and substrate specificity are unclear.
  • Understanding ADAM17 regulation is crucial for deciphering cellular signaling pathways.

Purpose of the Study:

  • To investigate the role of lipid rafts in ADAM17 localization and activity.
  • To elucidate the mechanism controlling ADAM17-dependent substrate shedding.

Main Methods:

  • Investigated ADAM17 localization within cholesterol-rich membrane microdomains (lipid rafts) during Golgi transport.
  • Utilized metalloproteinase inhibition and cholesterol depletion to assess ADAM17 activity.
  • Analyzed the presence of ADAM17 substrates (TNF, TNFR1, TNFR2) in lipid rafts.

Main Results:

  • ADAM17 prodomain cleavage by furin occurs within lipid rafts, sequestering its activity.
  • Metalloproteinase inhibition increases ADAM17 substrates in lipid rafts.
  • Cholesterol depletion enhances ADAM17-dependent shedding of its substrates.
  • Substrate distribution within lipid rafts suggests specific regulatory mechanisms.

Conclusions:

  • ADAM17 activity and substrate cleavage are regulated by its partitioning into lipid rafts.
  • Lipid rafts play a critical role in controlling ADAM17-mediated protein shedding.
  • Specific regulation of substrate entry into lipid rafts influences cleavage efficiency.

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