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Mal connects TLR2 to PI3Kinase activation and phagocyte polarization

Sandra Santos-Sierra1, Sachin D Deshmukh, Julia Kalnitski

  • 1Center for Pediatrics and Adolescent Medicine and Centre of Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg 79106, Germany.

The EMBO Journal
|July 4, 2009
PubMed

Insights

Toll-like receptor 2 (TLR2) signaling typically requires MyD88 and Mal adaptors. This study reveals a novel TLR2 pathway where Mal directly activates phosphoinositide 3-kinase (PI3K), independent of MyD88, to control inflammation.

Area of Science:

  • Immunology
  • Cellular Signaling
  • Microbiology

Background:

  • Toll-like receptor 2 (TLR2) recognizes bacterial lipoproteins, initiating inflammatory responses crucial for infection control.
  • TLR2-mediated signaling was thought to exclusively depend on myeloid differentiation primary response gene 88 (MyD88) and MyD88-adapter-like (Mal/TIRAP) adaptor proteins.

Purpose of the Study:

  • To investigate a novel TLR2 signaling pathway independent of MyD88.
  • To elucidate the specific role of Mal in TLR2-mediated responses.

Main Methods:

  • Stimulation of TLR2/6 heterodimers with diacylated bacterial lipoproteins.
  • Analysis of protein-protein interactions between Mal and phosphoinositide 3-kinase (PI3K) regulatory subunit p85alpha.
  • Assessment of PI3K activation, Akt phosphorylation, phosphatidylinositol(3,4,5)P3 (PIP(3)) generation, and macrophage polarization.

Main Results:

  • The Mal adaptor protein directly and inducibly interacts with the PI3K regulatory subunit p85alpha upon TLR2/6 stimulation.
  • This Mal-p85alpha interaction triggers PI3K-dependent Akt phosphorylation and PIP(3) generation, leading to macrophage polarization.
  • MyD88 is not essential for initial PI3K activation or Akt phosphorylation but cooperates with Mal for PIP(3) accumulation.
  • TLR2/1 signaling, unlike TLR2/6, does not require Mal or MyD88 for Akt phosphorylation.

Conclusions:

  • Mal acts as a specific link between the TLR2/6 heterodimer and the PI3K pathway.
  • This novel MyD88-independent pathway involving Mal, PI3K, and Akt plays a critical role in bacterial lipoprotein-induced macrophage polarization and inflammation.
  • The findings challenge the established model of TLR2 signaling and highlight pathway specificity based on TLR2 heterodimer composition.

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