The Rab11a GTPase controls Toll-like Receptor 4-induced Activation of Interferon Regulatory Factor-3 on Phagosomess

Husebye, H., Aune, M. H., Stenvik, J., Samstad, E., Skjeldal, F., Halaas, Ø., Nilsen, N. J., Stenmark, H., Latz, E., and Lien, E. (2010) Immunity 33, 583-596

Speaker: Wan-Ying Lin (林宛瑩)                                  Time: 13:10~14:00, Mar. 9, 2011

Commentator: Pei-Jane Tsai, Ph.D. (蔡佩珍老師)       Place: Room 601

Abstract:

       Toll-like receptor 4 (TLR4) is necessary for sensing Gram negative bacteria component lipopolysaccharide (LPS) and eliciting antibacterial response. TLR4 activation leads to two distinct signaling pathways. One pathway is mediated by Toll-interleukin 1 receptor (TIR) domain containing adaptor (TIRAP) and Myeloid differentiation primary-response gene 88 (MyD88) to activate NF-kB and MAP kinase and induce proinflammatory cytokine production. The other pathway is mediated by TIR-domain-containing adaptor protein inducing IFN-β (TRIF) and TRIF-related adaptor molecule (TRAM) to induce the interferon-b (IFN-b) expression (1). Rab11 is a small GTPase and highly concentrated in the perinuclear endocytic recycling compartment (ERC). Rab11a, a member of Rab11family, is best known for recycling previously internalized endosomal membrane to cell surface and for maintaining the area of plasma membrane (2). Rab11a has been reported to associate with phagocytosis and transport of tumor necrosis factor. In this study, the authors investigated the possible roles of Rab11a in controlling the trafficking of TLR4 to Gram-negative containing phagosomes and in regulating cytokine production. TLR4 was shown to colocalize with Rab11a in the ERC. After phagocytosis of E. coli, Rab11a, TLR4 and its signaling molecules TRAM and Interferon Regulatory Factor-3 (IRF-3) were recruited to E. coli. phagosomes. In Rab11a knockdown experiments, Rab11a was essential for recruitment of TLR4, TRAM and IRF-3 to E. coli. phagosomes. Silencing Rab11a also inhibited IRF-3 activation, whereas NF-kB activation was unaffected. In summary, Rab11a regulates the trafficking of TLR4, TRAM and IRF-3 to E. coli. phagosomes, leading to IRF-3 activation and IFN-b production.

References:

1. Takeuchi, O., and Akira, S. (2010) Cell 140, 805-820

2. Jordens, I., Marsman, M., Kuijl, C., and Neefjes, J. (2005) Traffic 6, 1070-1077