Toll-like receptor 4 signalling

throughout our lifetime microorganisms present in our environment constantly bombard us these invisible Invaders are in the air we breathe the food we eat and the water we drink in most cases we are able to resist infection a functioning immune system requires a delicate balance of inflammatory responses too little and we can be overwhelmed by infection too much and we can succumb to the immune response itself our first level of defense is the innate immune system this includes physical barriers of the skin mucosal and chemical barriers but there is more to the innate immune system when the anatomical level of defense is breached millions of microorganisms can gain access to our bodies the innate immune system is activated when pattern recognition receptors or PRS identify non self molecules known as pathogen Associated molecular patterns or pamps that are expressed on the surface of foreign microorganisms tolllike receptors or tlrs are a particularly important group of prrs human beings have 10 identified members of the tlr family let's examine the role of one of these PRS TL R4 and its pamp lipopolysaccharide or LPS in more detail inside a human blood vessel a maccrage searches for invading bacteria with its membranebound tlr4 tlr4 allows the maccrage to detect LPS a component of the cell wall of gram negative bacteria the mechanism of lipopolysaccharide recognition by tlr4 is complex and requires several accessory proteins a serum protein LPS binding protein binds to LPS monomers and traffics them to a protein called cd14 cd14 can be soluble or bound to the cells peripherally through a glycosyl phosphole inositol anchor cd14 delivers and loads LPS to the Ecto domain of tlr4 tlr4 is able to detect LPS with the help of an accessory protein called md2 homo dimerization of tlr4 ecto domains are induced when LPS binds to the complex of tlr4 cd14 and md2 the confirmational change of the Ecto domains initiates the dimerization the cytoplasmic tol il1 receptor or TI domain the tis provide a new scaffold that allows the recruitment of adapter proteins to form a postreceptor signaling complex the ti containing adapter protein myd88 recognizes the change in the ti domain of tlr4 and binds to this new receptor complex this results in a complex Cascade of signaling events which warns the cell of pathogen attack one of the key events in this pathway is the activation of the transcription Factor nuclear Factor Kappa b or NF Kappa B which is thought to be the major initiator of inflammation in a resting cell NF Kappa B is sequestered in the cytoplasm by its inhibitor inhibitor Kappa b or ippa B which masks the nuclear localization signal on NF Capa B signal transduction from the lps-bound tlr4 complex releases NF Capa B by phosphor I Capa B which tags it for Destruction and free NF Capa B so that it can translocate to the nucleus inside the nucleus NF Capa B seeks out its Target genes to initiate transcription by RNA polymerase Downstream effectors of the innate immune response such as cyto kindes and chemokines are synthesized and ultimately lead to an inflammatory response to block the growth of bacteria research in tlr4 mediated immune responses allow us to better understand immune system balance and will be essential to the design of new therapies for a range of immune related conditions

Channel: Immunology Toronto

Views: 107,781

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Id: GXECgTLGLtI

Length: 5min 5sec (305 seconds)

Published: Fri Jan 30 2015