title: The small GTPase Arf6 is essential for the Tram/Trif pathway in TLR4 signaling.
abstract: Recognition of lipopolysaccharides (LPS) by Toll-like receptor 4 (TLR4) at the plasma membrane triggers NF-κB activation through recruitment of the adaptor proteins Mal and MyD88. Endocytosis of the activated TLR4 allows recruitment of the adaptors Tram and Trif, leading to activation of the transcription factor IRF3 and interferon production. The small GTPase ADP-ribosylation factor 6 (Arf6) was shown to regulate the plasma membrane association of Mal. Here we demonstrate that inhibition of Arf6 also markedly reduced LPS-induced cytokine production in Mal(-/-) mouse macrophages. In this article, we focus on a novel role for Arf6 in the MyD88-independent TLR4 pathway. MyD88-independent IRF3 activation and IRF3-dependent gene transcription were strictly dependent on Arf6. Arf6 was involved in transport of Tram to the endocytic recycling compartment and internalization of LPS, possibly explaining its requirement for LPS-induced IRF3 activation. Together, these results show a critical role for Arf6 in regulating Tram/Trif-dependent TLR4 signaling.
authors.affiliation: From the Department of Medical Protein Research, Cytokine Receptor Lab, VIB, Ghent B-9000, Belgium.
authors.forename: Tim
authors.initials: T
authors.lastname: Van Acker
authors.forename: Sven
authors.initials: S
authors.lastname: Eyckerman
authors.forename: Lieselotte
authors.initials: L
authors.lastname: Vande Walle
authors.forename: Sarah
authors.initials: S
authors.lastname: Gerlo
authors.forename: Marc
authors.initials: M
authors.lastname: Goethals
authors.forename: Mohamed
authors.initials: M
authors.lastname: Lamkanfi
authors.forename: Celia
authors.initials: C
authors.lastname: Bovijn
authors.forename: Jan
authors.initials: J
authors.lastname: Tavernier
authors.forename: Frank
authors.initials: F
authors.lastname: Peelman
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins / Q000235:genetics / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
chemical_list: D000089982:ADP-Ribosylation Factor 6; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D008070:Lipopolysaccharides; C569027:Mal protein, mouse; C507780:Myd88 protein, mouse; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D053594:Myeloid Differentiation Factor 88; D018123:Receptors, Interleukin; C476416:Ticam2 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human; C000715727:Arf6 protein, mouse
keywords: Arf6; Cytokines/Interferon; Endocytosis; Innate Immunity; Lipopolysaccharide (LPS); Mal TIRAP; MyD88; TRIF; Toll-like Receptors (TLR)