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RhoA GTPase Activation by TLR2 and TLR3 Ligands: Connecting via Src to NF-B¹

Maria Manukyan^*, Perihan Nalbant, Sylvia Luxen^*, Klaus M. Hahn and Ulla G. Knaus^2,*

^* Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037; Center for Medical Biotechnology, University of Duisburg-Essen, Essen, Germany; and Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599

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-B, 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-B 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI35947 and GM37696 (to U.G.K.) and GM57464 (to K.M.H.).

² Address correspondence and reprint requests to Dr. Ulla G. Knaus, Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, IMM28, La Jolla, CA 92037. E-mail address: uknaus{at}scripps.edu

³ Abbreviations used in this paper: TRIF, TIR-domain-containing adapter-inducing IFN-β; EGF, epidermal growth factor; FRET, fluorescence resonance energy transfer; GEF, guanine nucleotide exchange factor; MEF, murine embryonic fibroblast; SALE, small airway lung epithelial; SI, Src kinase inhibitor I; siRNA, small interfering RNA.

⁴ The online version of this article contains supplemental material.

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