The Small GTPase Arf6 is Essential for the Tram/Trif Pathway in TLR4 Signaling

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2013 Dec 4

PMID 24297182

Citations 21

Authors

Tim Van Acker

Sven Eyckerman

Lieselotte Vande Walle

Sarah Gerlo

Marc Goethals

Mohamed Lamkanfi

Celia Bovijn

Jan Tavernier

Frank Peelman

Affiliations

Soon will be listed here.

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.

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