Integrin-nucleated Toll-like receptor (TLR) dimerization reveals subcellular targeting of TLRs and distinct mechanisms of TLR4 activation and signaling.
Toll-like receptors (TLRs) are activated by microbial structures. To investigate the mechanisms of TLR activation, the 10 human TLRs were expressed as chimeras with the integrin alphav and beta5 subunits. Co-expression of the alphav-TLR and beta5-TLR chimeras in 293T cells generated 10 TLR homodimers, but only TLR4/4 could effectively activate NF-kappaB. TLR4 monomers also activated NF-kappaB but it was enhanced upon homodimerization. The TLR homodimers showed differential surface/intracellular expression. In TLR heterodimers, only TLR2/1 and TLR2/6 were potent in NF-kappaB activation. NF-kappaB activation by TLR2/1, TLR2/6 and the TLR4 monomer, but not TLR4/4, was completely inhibited by dominant negative MyD88, suggesting that TLR4 homodimers and monomers could activate NF-kappaB through different mechanisms.
Zhang
Haifeng
H
National University Medical Institutes, Clinical Research Centre, Blk MD11, 10 Medical Drive, Singapore 117597, Singapore.
Tay
Puei Nam
PN
Cao
Weiping
W
Li
Wei
W
Lu
Jinhua
J
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation / Q000502:physiology; D002460:Cell Line; D019281:Dimerization; D029721:Drosophila Proteins; D006801:Humans; D039564:Integrin alphaV / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D039641:Integrin beta Chains / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016023:Integrins / Q000737:chemistry / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017385:Sequence Homology; D015398:Signal Transduction; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051216:Toll-Like Receptor 6; D051193:Toll-Like Receptors
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D029721:Drosophila Proteins; D039564:Integrin alphaV; D039641:Integrin beta Chains; D016023:Integrins; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C495368:TLR6 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051216:Toll-Like Receptor 6; D051193:Toll-Like Receptors; C084344:integrin beta5