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Related Experiment Videos

HDLs activate ADAM17-dependent shedding.

Edwige Tellier1, Matthias Canault, Marjorie Poggi

  • 1Inserm, U626, Marseilles, France.

Journal of Cellular Physiology
|September 6, 2007
PubMed
Summary
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High-density lipoproteins (HDLs) promote the shedding of tumor necrosis factor-alpha (TNF) and its receptors by altering lipid raft structure. This cholesterol efflux mechanism activates ADAM17, a key enzyme in transmembrane protein processing.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Molecular Medicine

Background:

  • ADAM17 (a disintegrin and metalloproteinase domain 17) is a metalloprotease crucial for cleaving transmembrane proteins like TNF and its receptors.
  • Previous studies indicated ADAM17 activity is sequestered in lipid rafts and that cholesterol depletion enhances substrate shedding, suggesting a role for membrane cholesterol dynamics.

Purpose of the Study:

  • To investigate whether high-density lipoprotein (HDL)-induced membrane cholesterol efflux influences the shedding activity of ADAM17 substrates.
  • To elucidate the mechanism by which HDL affects ADAM17-mediated protein processing.

Main Methods:

  • Treatment of various cell types and cell-free plasma membranes with HDLs and purified apoA1.
  • Assessment of ectodomain shedding of ADAM17 substrates (TNFR2, TNFR1, TNF).

Related Experiment Videos

  • Inhibition of ADAM17 activity and investigation of ABCA1 transporter involvement.
  • Analysis of cholesterol and protein content within lipid rafts.

    • Main Results:

    • HDLs significantly increased the shedding of TNFR2, TNFR1, and TNF across different cell types, an effect inhibited by ADAM17 inhibitors.
    • HDL-stimulated TNF release was observed even in cell-free membrane preparations.
    • Purified apoA1 enhanced TNF shedding in an ABCA1-dependent manner, highlighting the role of cholesterol efflux.
    • HDLs reduced cholesterol and ADAM17 levels in lipid rafts, promoting TNF cleavage in non-raft membrane regions.

    Conclusions:

    • HDLs modulate lipid raft composition and structure.
    • This alteration in lipid rafts leads to the activation of ADAM17-dependent processing of transmembrane substrates.
    • The findings reveal a novel mechanism linking HDL-mediated cholesterol efflux to the regulation of ADAM17 activity and substrate shedding.