TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-beta (Nat Immunol, 2008, 9:361-368)

報告日期: 2009/03/17
報告時間: 16:00/16:50
報告學生: 馬志遠
講評老師: 凌 斌

TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-β

Jonathan C Kagan, Tian Su, Tiffany Horng, Amy Chow, Shizuo Akira & Ruslan Medzhitov

Nat Immunol 9, 361-368 (2008).


Speaker: Chih-Yuan Ma                                       Date: 2009.3.17 (16:00-16:50)

Commentator: Pin Ling, Ph.D.                             Room: 602



Pattern-recognition receptors (PRRs) play important roles in innate immunity. They can recognize pathogen-associated molecular patterns (PAMPs) and in turn activate immune defense. Toll-like receptors (TLRs) belong to the family of PRRs and regulate innate immunity against microbial infection in humans. Toll-like receptor 4 (TLR4) is the well-characterized TLR and induces two distinct signaling pathways when stimulated with lipopolysaccharide (LPS). One is the TIRAP-MyD88 pathway which stimulates the production of proinflammatory cytokines, and the other is TRAM-TRIF pathway which elicit the expression of type I interferon. However, the reason why TLR4 uses these two different pathways in response to LPS is still unclear. In this study, the authors found that inhibition of endocytosis by a specific inhibitor of dynamin called dynasore could disrupt TRAM-TRIF-dependent signaling but not TIRAP-MyD88-dependent signaling. They also demonstrated that TRAM contains a bipartite localization motif that controls the subcellular distribution of TRAM and regulates TRAM-TRIF pathway. Taken together, they propose that TLR4 induces TRAM-TRIF signaling pathway from endosomal compartment and then triggers the expression of type I interferon. Furthermore, they found that TRAF3 is a critical factor in the production of interferon and the localization of TRAF3 regulates interferon-producing ability. This study provides a new model of TLR4 in the induction of type I interferon and demonstrates TRAF3 is an important molecule in the production of type I interferon.



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