RhoA GTPase activation by TLR2 and TLR3 ligands: connecting via Src to NF-kappa B.
Rho GTPases are essential regulators of signaling networks emanating from many receptors involved in innate or adaptive immunity. The Rho family member RhoA controls cytoskeletal processes as well as the activity of transcription factors such as NF-kappaB, C/EBP, and serum response factor. The multifaceted host cell activation triggered by TLRs in response to soluble and particulate microbial structures includes rapid stimulation of RhoA activity. RhoA acts downstream of TLR2 in HEK-TLR2 and monocytic THP-1 cells, but the signaling pathway connecting TLR2 and RhoA is still unknown. It is also not clear if RhoA activation is dependent on a certain TLR adapter. Using lung epithelial cells, we demonstrate TLR2- and TLR3-triggered recruitment and activation of RhoA at receptor-proximal cellular compartments. RhoA activity was dependent on TLR-mediated stimulation of Src family kinases. Both Src family kinases and RhoA were required for NF-kappaB activation, whereas RhoA was dispensable for type I IFN generation. These results suggest that RhoA plays a role downstream of MyD88-dependent and -independent TLR signaling and acts as a molecular switch downstream of TLR-Src-initiated pathways.
Manukyan
Maria
M
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
Nalbant
Perihan
P
Luxen
Sylvia
S
Hahn
Klaus M
KM
Knaus
Ulla G
UG
D000818:Animals; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D008024:Ligands; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000378:metabolism* / Q000502:physiology; D051196:Toll-Like Receptor 3 / Q000378:metabolism* / Q000502:physiology; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism* / Q000502:physiology
D008024:Ligands; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C495342:TLR2 protein, human; C495344:TLR3 protein, human; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; C066737:RHOA protein, human; D019061:src-Family Kinases; D020742:rhoA GTP-Binding Protein