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The small GTPase Arf6 is essential for the Tram/Trif pathway in RLR4 signaling

Tim Van Acker (UGent) , Sven Eyckerman (UGent) , Lieselotte Vande Walle (UGent) , Sarah Gerlo (UGent) , Marc Goethals (UGent) , Mohamed Lamkanfi (UGent) , Celia Bovijn (UGent) , Jan Tavernier (UGent) and Frank Peelman (UGent)
(2014) JOURNAL OF BIOLOGICAL CHEMISTRY. 289(3). p.1364-1376
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Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
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.
Keywords
RIBOSYLATION FACTOR 6, MYD88 ADAPTER-LIKE, RECEPTOR-MEDIATED PHAGOCYTOSIS, INTERFERON REGULATORY FACTOR-3, Cytokines/Interferon, NF-KAPPA-B, Mal TIRAP, MyD88, TRIF, Toll-like Receptors (TLR), Arf6, Lipopolysaccharide (LPS), Endocytosis, Innate Immunity, PLASMA-MEMBRANE, ACTIVATING PROTEIN, IKK-EPSILON, MOLECULE, REQUIREMENT

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Citation

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Chicago
Van Acker, Tim, Sven Eyckerman, Lieselotte Vande Walle, Sarah Gerlo, Marc Goethals, Mohamed Lamkanfi, Celia Bovijn, Jan Tavernier, and Frank Peelman. 2014. “The Small GTPase Arf6 Is Essential for the Tram/Trif Pathway in RLR4 Signaling.” Journal of Biological Chemistry 289 (3): 1364–1376.
APA
Van Acker, Tim, Eyckerman, S., Vande Walle, L., Gerlo, S., Goethals, M., Lamkanfi, M., Bovijn, C., et al. (2014). The small GTPase Arf6 is essential for the Tram/Trif pathway in RLR4 signaling. JOURNAL OF BIOLOGICAL CHEMISTRY, 289(3), 1364–1376.
Vancouver
1.
Van Acker T, Eyckerman S, Vande Walle L, Gerlo S, Goethals M, Lamkanfi M, et al. The small GTPase Arf6 is essential for the Tram/Trif pathway in RLR4 signaling. JOURNAL OF BIOLOGICAL CHEMISTRY. 2014;289(3):1364–76.
MLA
Van Acker, Tim, Sven Eyckerman, Lieselotte Vande Walle, et al. “The Small GTPase Arf6 Is Essential for the Tram/Trif Pathway in RLR4 Signaling.” JOURNAL OF BIOLOGICAL CHEMISTRY 289.3 (2014): 1364–1376. Print.
@article{4326746,
  abstract     = {Recognition of lipopolysaccharides (LPS) by Toll-like receptor 4 (TLR4) at the plasma membrane triggers NF-\ensuremath{\kappa}B 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.},
  author       = {Van Acker, Tim and Eyckerman, Sven and Vande Walle, Lieselotte and Gerlo, Sarah and Goethals, Marc and Lamkanfi, Mohamed and Bovijn, Celia and Tavernier, Jan and Peelman, Frank},
  issn         = {0021-9258},
  journal      = {JOURNAL OF BIOLOGICAL CHEMISTRY},
  language     = {eng},
  number       = {3},
  pages        = {1364--1376},
  title        = {The small GTPase Arf6 is essential for the Tram/Trif pathway in RLR4 signaling},
  url          = {http://dx.doi.org/10.1074/jbc.M113.499194},
  volume       = {289},
  year         = {2014},
}

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