Mal connects TLR2 to PI3Kinase activation and phagocyte polarization.
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.
Santos-Sierra
Sandra
S
Center for Pediatrics and Adolescent Medicine and Centre of Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg 79106, Germany.
Deshmukh
Sachin D
SD
Kalnitski
Julia
J
Küenzi
Peter
P
Wymann
Matthias P
MP
Golenbock
Douglas T
DT
Henneke
Philipp
P
D000818:Animals; D002460:Cell Line; D016764:Cell Polarity; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D015778:Minor Histocompatibility Antigens; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism*
C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; D015778:Minor Histocompatibility Antigens; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D017853:Phosphotransferases (Alcohol Group Acceptor); C402182:phosphatidylinositol phosphate 4-kinase