It is interesting to speculate that p and p may be processed by a similar mechanism in response to inducers that have yet to be identified.In mammals the NFB p protein has a protein kinase A phosphorylation site on serine, and phosphorylation of this residue is required for efficient binding to the transcriptional activator protein CBP.Similar to the situation with PKA, IB protects p from phosphorylation by constitutively active CKII, but signaldependent degradation of IB exposes the p phosphorylation site to CKII activity.CKII was shown to associate with p in vivo, and this association decreased upon TNF induction.Moreover, CKII phosphorylates p at serine in vitro, and inhibitors of CKII block phosphorylation and transcriptional <a href="http://www.targetmol.com/compound/Carbimazole"></a>
activation in vivo. Similarly, overexpression of IKK led to the phosphorylation of p at serine. In any case, there is ample evidence to support the idea that p phosphorylation is critical for full NFB activation, and this activation can be uncoupled functionally from IB phosphorylation and degradation.In all these receptors, the TIR domain mediates activation of intracellular signaling pathways.LPS is a potent activator of innate immunity, and excessive exposure to LPS, or endotoxin, causes serious pathological effects. Furthermore, TLR appears to directly bind to LPS.Lipid A is the active component of LPS and deacetylated lipid A is immunostimulatory in murine but not human systems.Two groups recently demonstrated that expression of mTLR, but not hTLR, enabled recognition and signaling in response to deacetylated lipid A. In addition to TLR, two other extracellular proteins are involved in LPS recognition.CD, a GPI anchored protein, has long been known to bind to LPS and is required for LPS signaling. MD interacts with extracellular domain of TLR and is necessary for LPS signaling. This argues that TLR, CD, and MD bind to LPS, possibly in a tetrameric complex.Interestingly, CD and TLR have also been implicated in the immune recognition of proteins encoded by viral pathogens such as RSV. This is believed to be accomplished by the correspondingly restricted activation of a serine protease cascade consisting of the products of the nudel, gastrulation defective, snake, and easter genes. Activation of this protease cascade is regulated by the products of the windbutel and pipe genes.Interestingly, pipe is the only one of the dorsal group genes expressed in a spatially restricted manner, on the ventral side of the embryo.The spatially restricted expression of pipe is therefore thought to be the key signal activating the entire cascade in the correct location to establish ventral cell fates. The pipe gene product is a heparinsulfotransferase, and it has been proposed to create a heparinmodified proteoglycan that is required for local activation of the protease cascade.The identity of these proteases and the mechanism of their activation remain unknown.In fact, mutants in the TLR receptor wheeler have some defects in antibacterial immune signaling.However, induction of the other antibacterial peptides, such as diptericin, occurs at near wildtype levels in wheeler mutants.Therefore, w is not strictly required for the antibacterial immune response and cannot be the sole LPS receptor. DGNBP does not have transmembrane or intracellular domain and, like CD, is held at the membrane by a GPI anchor.