UNC93B1 mediates differential trafficking of endosomal TLRs

Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology , University of California, Berkeley , Berkeley , United States.
eLife Sciences (Impact Factor: 9.32). 02/2013; 2(2):e00291. DOI: 10.7554/eLife.00291
Source: PubMed


UNC93B1, a multipass transmembrane protein required for TLR3, TLR7, TLR9, TLR11, TLR12, and TLR13 function, controls trafficking of TLRs from the endoplasmic reticulum (ER) to endolysosomes. The mechanisms by which UNC93B1 mediates these regulatory effects remain unclear. Here, we demonstrate that UNC93B1 enters the secretory pathway and directly controls the packaging of TLRs into COPII vesicles that bud from the ER. Unlike other COPII loading factors, UNC93B1 remains associated with the TLRs through post-Golgi sorting steps. Unexpectedly, these steps are different among endosomal TLRs. TLR9 requires UNC93B1-mediated recruitment of adaptor protein complex 2 (AP-2) for delivery to endolysosomes while TLR7, TLR11, TLR12, and TLR13 utilize alternative trafficking pathways. Thus, our study describes a mechanism for differential sorting of endosomal TLRs by UNC93B1, which may explain the distinct roles played by these receptors in certain autoimmune diseases. DOI:

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    • "UNC93B1 also regulates excessive TLR7 signaling by recruiting TLR9 to counteract TLR7 (Fukui et al., 2009). In the case of TLR9 trafficking, interaction with the adapter protein-2 complex is also required (Lee et al., 2013; Chow et al., 2015). Protein associated with Toll-like receptor 4 is another resident protein of the endoplasmic reticulum that does not discriminate between intracellular and cell surface TLRs and plays a role in the exit of TLR1, TLR2, TLR4, TLR7, and TLR9 from the endoplasmic reticulum and their trafficking to plasma membrane and endosomes (Takahashi et al., 2007). "
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    ABSTRACT: Toll-like receptors (TLRs) are components of the innate immune system that respond to exogenous infectious ligands (pathogen-associated molecular patterns, PAMPs) and endogenous molecules that are released during host tissue injury/death (damage-associated molecular patterns, DAMPs). Interaction of TLRs with their ligands leads to activation of downstream signaling pathways that induce an immune response by producing inflammatory cytokines, type I interferons (IFN), and other inflammatory mediators. TLR activation affects vascular function and remodeling, and these molecular events prime antigen-specific adaptive immune responses. Despite the presence of TLRs in vascular cells, the exact mechanisms whereby TLR signaling affects the function of vascular tissues are largely unknown. Cardiovascular diseases are considered chronic inflammatory conditions, and accumulating data show that TLRs and the innate immune system play a determinant role in the initiation and development of cardiovascular diseases. This evidence unfolds a possibility that targeting TLRs and the innate immune system may be a novel therapeutic goal for these conditions. TLR inhibitors and agonists are already in clinical trials for inflammatory conditions such as asthma, cancer, and autoimmune diseases, but their study in the context of cardiovascular diseases is in its infancy. In this article, we review the current knowledge of TLR signaling in the cardiovascular system with an emphasis on atherosclerosis, hypertension, and cerebrovascular injury. Furthermore, we address the therapeutic potential of TLR as pharmacological targets in cardiovascular disease and consider intriguing research questions for future study.
    Preview · Article · Dec 2015 · Pharmacological reviews
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    • "All TLRs are synthesized in the ER, traffic to the Golgi, and are recruited to the cell surface or to intracellular compartments such as endosomes. Intracellular localization of TLRs is thought to be critical for ligand recognition as well as for preventing TLRs from coming into contact with self-nucleic acids, which could cause autoimmunity (26–29). The multi-pass transmembrane protein UNC93B1 controls the trafficking of intracellular TLRs from the ER to endosomes. "
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    ABSTRACT: Toll-like receptors (TLRs) play crucial roles in the innate immune system by recognizing pathogen-associated molecular patterns derived from various microbes. TLRs signal through the recruitment of specific adaptor molecules, leading to activation of the transcription factors NF-κB and IRFs, which dictate the outcome of innate immune responses. During the past decade, the precise mechanisms underlying TLR signaling have been clarified by various approaches involving genetic, biochemical, structural, cell biological, and bioinformatics studies. TLR signaling appears to be divergent and to play important roles in many aspects of the innate immune responses to given pathogens. In this review, we describe recent progress in our understanding of TLR signaling regulation and its contributions to host defense.
    Full-text · Article · Sep 2014 · Frontiers in Immunology
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    • "Localization of TLR9 to the cell membrane has been reported in HEK293 as a consequence of stimulation with CpG DNA [5] on human peripheral blood mononuclear cells (PBMC) stimulated by LPS [45] and on mouse intestinal epithelial cells after exposure of cells to DNA from pathogenic Salmonella enterica [46]. Recently it has been reported that Unc93b1 is also required for the surface appearance of mouse TLR9 [47], however, we could not detect the surface localization of TLR9 on HEK293 cells. The reason for those differences may be that we investigated localization of the human and not mouse TLR9. "
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    ABSTRACT: Toll-like receptor 3 (TLR3) is a dsRNA sensing receptor that is localized in the cellular compartments but also at the plasma membrane. Overexpression of UNC93B1 promoted localization of TLR3, but not other nucleic acid sensing TLRs, to the plasma membrane. Here we show that UNC93B1 itself is localized at the plasma membrane. We investigated the role of different domains of TLR3 on cell signaling by preparing chimeric receptors between TLR3 and TLR9 where each of the transmembrane segments or cytosolic domains has been exchanged. While the ectodomain completely governs ligand specificity and the cytosolic TIR domain determines the engagement of the signaling adapters as well as the potentiation of receptor activation by UNC93B1, the ectodomain but not transmembrane segment or cytosolic domain determines plasma membrane localization of TLR3. Nevertheless, TLR3 receptor and ligand endocytosis as well as endosomal acidification are important for the robust signaling of TLR3.
    Full-text · Article · Mar 2014 · PLoS ONE
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