【信息】The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling
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Nature Reviews Immunology 7, 353-364 (May 2007) | doi:10.1038/nri2079
The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling
Luke A. J. O'Neill1 & Andrew G. Bowie1 About the authors
Summary
TLR (Toll-like receptor) signal transduction involves five adaptor proteins. MyD88 (myeloid differentiation primary-response gene 88), MAL (MyD88-adaptor-like protein), TRIF (TIR-domain-containing adaptor protein inducing interferon- (IFN)) and TRAM (TRIF-related adaptor molecule) are recruited to TIR (Toll/interleukin-1 (IL-1) receptor) domains to initiate signalling, whereas SARM (sterile - and armadillo-motif-containing protein) inhibits TRIF-dependent signalling.
MyD88 is the universal adaptor used by all TLRs with the exception of TLR3. MyD88 couples to pathways that lead to the activation of transcription factors such as NF-B (nuclear factor-B), IRF1 (IFN-regulatory factor 1), IRF5 and IRF7. It is also involved in TLR-independent signals activated by IL-1, IL-18 and IFN.
MAL is required to recruit MyD88 to TLR2 and TLR4. It is membrane associated through a phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2)-binding domain and is subject to regulation by Bruton's tyrosine kinase and SOCS1 (suppressor of cytokine signalling 1), which interacts with MAL causing it to be degraded.
TRIF is used by TLR3, and leads to the activation of IRF3 through TBK1 (TRAF-family-member-associated NF-B activator-binding kinase 1). It is also involved in the NF-B activation pathway, which it achieves through recruitment of RIP1 (receptor-interacting protein 1). TRIF has also be shown to mediate apoptosis through RIP1.
TRAM is used only by TLR4, and its main function is recruitment of TRIF. TRAM is membrane localized through a myristic-acid group, which is attached to its amino terminus. It is subject to regulation by protein kinase C.
SARM is a negative regulator of TRIF, and therefore serves to regulate TLR3 and TLR4 signalling.
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Nature Reviews Immunology 7, 353-364 (May 2007) | doi:10.1038/nri2079
The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling
Luke A. J. O'Neill1 & Andrew G. Bowie1 About the authors
Summary
TLR (Toll-like receptor) signal transduction involves five adaptor proteins. MyD88 (myeloid differentiation primary-response gene 88), MAL (MyD88-adaptor-like protein), TRIF (TIR-domain-containing adaptor protein inducing interferon- (IFN)) and TRAM (TRIF-related adaptor molecule) are recruited to TIR (Toll/interleukin-1 (IL-1) receptor) domains to initiate signalling, whereas SARM (sterile - and armadillo-motif-containing protein) inhibits TRIF-dependent signalling.
MyD88 is the universal adaptor used by all TLRs with the exception of TLR3. MyD88 couples to pathways that lead to the activation of transcription factors such as NF-B (nuclear factor-B), IRF1 (IFN-regulatory factor 1), IRF5 and IRF7. It is also involved in TLR-independent signals activated by IL-1, IL-18 and IFN.
MAL is required to recruit MyD88 to TLR2 and TLR4. It is membrane associated through a phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2)-binding domain and is subject to regulation by Bruton's tyrosine kinase and SOCS1 (suppressor of cytokine signalling 1), which interacts with MAL causing it to be degraded.
TRIF is used by TLR3, and leads to the activation of IRF3 through TBK1 (TRAF-family-member-associated NF-B activator-binding kinase 1). It is also involved in the NF-B activation pathway, which it achieves through recruitment of RIP1 (receptor-interacting protein 1). TRIF has also be shown to mediate apoptosis through RIP1.
TRAM is used only by TLR4, and its main function is recruitment of TRIF. TRAM is membrane localized through a myristic-acid group, which is attached to its amino terminus. It is subject to regulation by protein kinase C.
SARM is a negative regulator of TRIF, and therefore serves to regulate TLR3 and TLR4 signalling.
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