Abstract
Clathrin-dependent endocytic pathway is crucial for cell entry of extracellular pathogens and their components. The innate immune system utilizes this pathway to detect pathogen-associated molecular patterns (PAMPs) within endosomes. In the clathrin-mediated endocytosis, cargo selection depends on AP-2 adaptor and its accessory proteins, but the molecular mechanism of PAMP selection to be internalized is largely unknown. The endosomal Toll-like receptors (TLRs) 3, 7, 8, and 9 recognize viral or bacterial nucleic acids, as well as host-derived nucleic acids incorporated into the endosomal compartments, where type I interferon (IFN)-producing signals are arisen. In addition, lipopolysaccharide (LPS) receptor TLR4 transmits signals to produce IFN-b from endosomes after the clathrin-dependent endocytosis of LPS-TLR4. The cytosolic protein Raftlin that possesses membrane-anchoring motif mediates cellular uptake of TLR3/4 ligands in human cells through association with clathrin-AP-2 complex. Raftlin was first identified as a major raft protein in B cells that modulates B-cell or T-cell receptor-mediated signaling. In this review, we will focus on the Raftlin function in innate immunity and discuss the molecular mechanisms of cellular uptake and delivery of TLR ligands.
Highlights
Innate immune system is essential for induction of adaptive immunity
In the clathrin-mediated endocytosis, cargo selection depends on AP-2 adaptor and its accessory proteins, but the molecular mechanism of pathogen-associated molecular patterns (PAMPs) selection to be internalized is largely unknown
In vitro transcribed dsRNAs (100 bp~1000bp) that are functional when directly delivered to endosomes are unable to activate TLR3 when extracellulary added to human myeloid dendritic cells (DCs) [43], suggesting the failure of dsRNA uptake in contrast to poly(I:C)
Summary
Innate immune system is essential for induction of adaptive immunity. A variety of soluble and membrane-bound pattern-recognition receptors (PRRs) have been provided to sense microbial infection, which elicit anti-microbial immune responses [1,2,3]. Toll-like receptors (TLRs), a type I transmembrane protein family, recognize pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS), peptidoglycan and viral nucleic acids, and transmit signals linking innate and adaptive immunity [3]. Among human TLRs 1-10, the nucleic acid-sensing TLRs 3, 7, 8 and 9 localize to the endosomal compartments, where they encounter the incorporated viral- or host-derived nucleic acids and induce type I interferon (IFN) and proinflammatory. Cell-surface TLR4 is internalized in the clathrin- and dynamin-dependent manner after the binding to LPS [12] to induce IFN-. We have reported that the cytosolic protein Raftlin that possesses membrane-anchoring motif mediates cellular uptake of poly(I:C), CpG ODNs and LPS in human dendritic cells (DCs), macrophages and epithelial cells through association with clathrin-AP-2 complex [16,17]. We will summarize the molecular mechanisms of exNA internalization and focus on the role of Raftlin in the regulation of endosomal TLR signaling
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