博士生课程固有紧免疫模式识别.ppt

Conserved pathways in innate immunity in Drosophila and mammals. Examples chosen are, left, the induction of the antifungal gene drosomycin by binding of processed Spaetzle protein to the transmembrane receptor Toll and, right, activation of costimulatory protein genes by binding of a LPS-LBP-CD14 complex to a human Toll homolog, TLR4. DD, death domain; KD, kinase domain; LRR, leucine-rich domain; TIR, Toll/IL-1 receptor homology domain Negative regulation of Toll-like receptor 4 (TLR4) signaling. Proteins interfering with primary TLR signaling and/or acting at early times after TLR stimulation are in pink, and those acting in a negative feedback mechanism and/or at late times are in green. Soluble TLR4 (sTLR4) may act as a decoy receptor to interfere with signal generation. The following factors negatively regulate TLR4 signaling: Toll/IL-1R homology (TIR) domain-containing transmembrane proteins ST2L (by sequestering MyD88 and TIRAP) and SIGIRR (by possibly interfering with the assembly of TLR signalosomes via interaction with TLR4, IRAK, and TRAF6); TRAILR, a tumor necrosis factor (TNF) superfamily member (by stabilizing IκBα at later times after TLR stimulation); MD1-associated RP105, a TLR homolog lacking a signaling domain (by interfering with the formation of the lipopolysaccharide (LPS)-signaling receptor complex TLR4-MD2); MyD88s, a splice variant of MyD88 (by preventing recruitment of IRAK4 to the TLR signaling complex); IRAKM, a homolog of IRAK1 (perhaps by inhibiting the dissociation of IRAK1 and IRAK4 from the TLR signaling complex); the ubiquitin-modulating enzymes A20 (by cleaving the ubiquitin chain of TRAF6) and TRIAD3A (by binding to the cytoplasmic domain of TLR4 and stimulating its ubiquitin-dependent degradation). Schematic showing the primary translation products of interleukin-1 (IL-1) family mRNAs, their processing enzymes (when known), the biologically relevant forms of the cytokines, the receptors they use (when known) and molecules that r