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PI3Kδ keeps TLR4 signalling on track

Nature Reviews Immunology volume 12, pages 744–745 (2012)Cite this article

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Phosphatidylinositol (PtdIns) membrane lipids interact with polybasic domains on adaptor and signalling proteins to promote the membrane localization or activation of these proteins. For example, the interaction of TIRAP with phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) is required for its recruitment to the plasma membrane, and the interaction of AKT with phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) is essential for AKT phosphorylation. The lipid kinase activity of class I PI3Ks (including PI3Kδ) converts PtdIns(4,5)P2 into PtdIns(3,4,5)P3, thereby affecting PtdIns dynamics and thus many cellular processes. As PI3Kδ is highly expressed by leukocytes, the authors studied its contribution to TLR4 signalling.

The lack of PI3Kδ lipid kinase activity in dendritic cells (DCs) from PI3Kδ-null mice resulted in low PtdIns(3,4,5)P3 and phosphorylated AKT levels, and in reduced TLR4 internalization following DC stimulation with the TLR4 ligand lipopolysaccharide (LPS), indicating that PI3Kδ is involved in TLR4 signalling. Moreover, PI3Kδ was shown to be recruited to the TLR4–TIRAP–MYD88 signallosome following LPS treatment. Neither the inhibition of other PI3K isoforms nor the genetic deletion of Trif affected AKT phosphorylation downstream of TLR4 activation, suggesting that PI3Kδ is specifically involved in TLR4 signalling through its recruitment to the early TLR4–TIRAP–MYD88 complex.

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ORIGINAL RESEARCH PAPER

  1. Aksoy, E. et al. The p110δ isoform of the kinase PI(3)K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock. Nature Immunol. 30 Sep 2012 (doi:10.1038/ni.2426)

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  1. Maria Papatriantafyllou
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Papatriantafyllou, M. PI3Kδ keeps TLR4 signalling on track. Nat Rev Immunol 12, 744–745 (2012). https://doi.org/10.1038/nri3330

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