AsialoGM1 and TLR5 cooperate in flagellin-induced nucleotide signaling to activate Erk1/2.
Bacterial flagellin can interact with both Toll-like receptor 5 (TLR5) and the cell surface glycolipid, asialoGM1, to activate an innate immune response. The induction of mucin by flagellin in human lung epithelial cells (NCIH292) is dependent on asialoGM1 ligation, ATP receptor signaling, Ca2+ mobilization, and Erk1/2 activation. Conversely, the activation of NF-kappaB by flagellin is dependent on signaling through TLR5. These results prompted us to ask whether the flagellin-induced TLR5 signaling pathway was intersecting with or mutually independent of the nucleotide receptor pathway activated downstream of asialoGM1. Herein, we demonstrate that the release of ATP induced by flagellin is dependent on a Toll signaling cascade. Although Toll was able to activate NF-kappaB in the absence of extracellular ATP, Toll required ATP to activate Erk1/2. These results suggest interdependence between the asialoGM1 and TLR5 pathways and reveal a previously unsuspected role for autocrine extracellular ATP signaling in TLR signaling.
McNamara
Nancy
N
Department of Anatomy, niversity of California, San Francisco, CA 94143-0452, USA. namara@ucsf.edu
Gallup
Marianne
M
Sucher
Anatol
A
Maltseva
Inna
I
McKemy
David
D
Basbaum
Carol
C
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism; D005408:Flagellin / Q000378:metabolism*; D005677:G(M1) Ganglioside / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000201:enzymology / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D051198:Toll-Like Receptor 5 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D018048:Receptors, Purinergic P2; D011993:Recombinant Fusion Proteins; C495346:TLR5 protein, human; D051198:Toll-Like Receptor 5; D005408:Flagellin; D005677:G(M1) Ganglioside; C018835:asialo GM1 ganglioside; D000255:Adenosine Triphosphate; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002118:Calcium