Location, location, location: is membrane partitioning everything when it comes to innate immune activation?
Triantafilou M, Lepper PM, Olden R, Dias IS, Triantafilou K.


Abstract

In the last twenty years, the general view of the plasma membrane has changed from a homogeneous arrangement of lipids to a mosaic of microdomains. It is currently thought that islands of highly ordered saturated lipids and cholesterol, which are laterally mobile, exist in the plane of the plasma membrane. Lipid rafts are thought to provide a means to explain the spatial segregation of certain signalling pathways emanating from the cell surface. They seem to provide the necessary microenvironment in order for certain specialised signalling events to take place, such as the innate immune recognition. The innate immune system seems to employ germ-lined encoded receptors, called pattern recognition receptors (PRRs), in order to detect pathogens. One family of such receptors are the Toll-like receptors (TLRs), which are the central "sensing" apparatus of the innate immune system. In recent years, it has become apparent that TLRs are recruited into membrane microdomains in response to ligands. These nanoscale assemblies of sphingolipid, cholesterol, and TLRs stabilize and coalesce, forming signalling platforms, which transduce signals that lead to innate immune activation. In the current paper, we will investigate all past and current literature concerning recruitment of extracellular and intracellular TLRs into lipid rafts and how this membrane organization modulates innate immune responses.


Activation of TLRs and adjuvant receptors on cell surface before and after stimulation by bacterial products. (a) TLR2 forms heterodimers with TLR1 and TLR6 on the cell surface and these heterodimer preexist and are not induced by the ligand. These heterodimers do not reside in lipid rafts before stimulation but are recruited to lipid rafts upon stimulation. This process is independent of signaling and facilitates the trafficking of TLRs from the cell surface to the Golgi. (b) TLR2/6 heterodimers are recruited within lipid rafts and associate with lipid raft-resident proteins CD14 and CD36 upon ligand stimulation. Binding of an appropriate microbial substance leads to energy-dependent clustering of heterotypic receptors and activation of intracellular signaling cascades that lead via NF-κB to the production and secretion of proinflammatory cytokines.

Activation of TLRs in endosomes. Various TLRs recognize microbial patterns within the endosome. TLR7 and 8 recognize ssRNA, whereas TLR9 recognises CpG DNA. As nucleic acid recognition bears a potential source for the induction of autoimmunity, TLR7 and 9 exist in a full-length and truncated version, where the ectodomain is cleaved. Only the endosomally processed forms are capable to recruit MyD88 and to induce signaling. Transport from the endoplasmatic reticulum (ER) is facilitated by UNC93B1 (a). Ligation of TLR7 by ssRNA leads to clustering within a lipid raft at the endosomal membrane and activation of intracellular signaling cascades that lead via NF-κB to production and secretion of proinflammatory cytokines (b).

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