Mal connects TLR2 to PI3Kinase activation and phagocyte polarization

UMMS Affiliation

Department of Medicine, Division of Infectious Disease & Immunology

Publication Date


Document Type



Immunity | Immunology and Infectious Disease | Immunology of Infectious Disease | Infectious Disease | Virology


The recognition of bacterial lipoproteins by toll-like receptor (TLR) 2 is pivotal for inflammation initiation and control in many bacterial infections. TLR2-dependent signalling is currently believed to essentially require both adaptor proteins MyD88 (myeloid differentiation primary response gene 88) and Mal/TIRAP (MyD88-adapter-like/TIR-domain-containing adaptor protein). TLR2-dependent, but MyD88-independent responses have not been described yet. We report here on a novel-signalling pathway downstream of TLR2, which does not adhere to the established model. On stimulation of the TLR2/6 heterodimer with diacylated bacterial lipoproteins, Mal directly interacts with the regulatory subunit of phosphoinositide 3-kinase (PI3K), p85alpha, in an inducible fashion. The Mal-p85alpha interaction drives PI3K-dependent phosphorylation of Akt, phosphatidylinositol(3,4,5)P3 (PIP(3)) generation and macrophage polarization. MyD88 is not essential for PI3K activation and Akt phosphorylation; however, cooperates with Mal for PIP(3) formation and accumulation at the leading edge. In contrast to TLR2/6, TLR2/1 does not require Mal or MyD88 for Akt phosphorylation. Hence, Mal specifically connects TLR2/6 to PI3K activation, PIP(3) generation and macrophage polarization.

DOI of Published Version



EMBO J. 2009 Jul 22;28(14):2018-27. doi: 10.1038/emboj.2009.158. Epub 2009 Jul 2. Link to article on publisher's site

Journal/Book/Conference Title

The EMBO journal

Related Resources

Link to Article in PubMed

PubMed ID