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Interleukin-6 signaling requires EHD1-mediated alteration of membrane rafts

Joo Hong Woo1, Soo Jung Park1, Sang Myun Park2,3

  • 1Inflamm-aging Translational Research Center, Ajou University School of Medicine, Suwon, Korea.

The FEBS Journal
|April 16, 2022
PubMed

Insights

Interleukin-6 (IL-6) signaling relies on cholesterol-rich membrane rafts. These rafts, specifically D4 rafts, act as platforms for IL-6 receptor assembly and function, regulated by EHD1 protein.

Area of Science:

  • Cell Biology
  • Immunology
  • Molecular Signaling

Background:

  • Interleukin-6 (IL-6) is a cytokine implicated in numerous inflammatory diseases.
  • IL-6 signaling occurs via classic signaling (membrane-bound IL-6 receptor α) or trans-signaling (soluble IL-6 receptor α), both involving gp130.
  • The precise role of membrane rafts, particularly cholesterol-dependent rafts, in regulating IL-6 receptor complex formation and signaling remains largely undefined.

Purpose of the Study:

  • To investigate the role of membrane cholesterol and lipid rafts in IL-6 classic signaling and trans-signaling.
  • To elucidate how membrane raft composition influences the assembly and function of IL-6 receptor complexes.
  • To identify proteins involved in mediating IL-6 signaling through membrane rafts.

Main Methods:

  • Super-resolution fluorescence imaging utilizing perfringolysin O D4 fragments to identify cholesterol-rich membrane rafts.
  • Analysis of membrane raft alterations induced by IL-6 and hyper-IL-6 (IL-6 fused with soluble IL-6Rα).
  • Assessment of IL-6 receptor (IL-6Rα and gp130) clustering and STAT3 phosphorylation within specific raft domains.
  • Investigation of the role of Eps15 homology domain-containing protein 1 (EHD1) in IL-6 signaling complex formation.

Main Results:

  • Both IL-6 classic signaling and trans-signaling are dependent on membrane cholesterol.
  • IL-6 and hyper-IL-6 induce the formation of D4-positive rafts (D4 rafts) without altering cholera toxin subunit B-positive rafts (CTB rafts).
  • IL-6 receptor complex assembly (IL-6Rα and gp130 clustering) and STAT3 phosphorylation occur within these D4 rafts.
  • EHD1 was identified as a key mediator in the formation of functional IL-6 receptor complexes via D4 rafts.

Conclusions:

  • Cholesterol-rich D4 rafts serve as critical platforms for the assembly of functional IL-6 receptor complexes.
  • The EHD1-mediated alteration of membrane rafts represents a novel regulatory mechanism for IL-6 signaling.
  • Understanding this mechanism could offer new therapeutic targets for IL-6-mediated inflammatory diseases.

Keywords:
EHD1IL-6STAT3inflammationmembrane raft

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