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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    • "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.
    Frontiers in Immunology 09/2014; 5(461):461. DOI:10.3389/fimmu.2014.00461
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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.
    PLoS ONE 03/2014; 9(3):e92391. DOI:10.1371/journal.pone.0092391 · 3.23 Impact Factor
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    • "In addition, differential recruitment of adaptor protein complexes (AP) affects post-Golgi trafficking of endosomal TLR. While AP-2 recruitment by TLR9 enables its translocation from the plasma membrane to the endolysosomal compartment, TLR7 trafficking is independent of AP-2 and does not involve transient localization to the plasma membrane, but instead is dependent on AP-4 recruitment (Lee et al., 2013). TLR3 trafficking is again distinct from TLR7 and TLR9 and is independent of PRAT4A and not affected by mutations in UNC93B1 that impair TLR7 and TLR9 trafficking (Takahashi et al., 2007; Fukui et al., 2011). "
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    ABSTRACT: The innate immune system has evolved endosomal and cytoplasmic receptors for the detection of viral nucleic acids as sensors for virus infection. Some of these pattern recognition receptors (PRR) detect features of viral nucleic acids that are not found in the host such as long stretches of double-stranded RNA (dsRNA) and uncapped single-stranded RNA (ssRNA) in case of Toll-like receptor (TLR) 3 and RIG-I, respectively. In contrast, TLR7/8 and TLR9 are unable to distinguish between viral and self-nucleic acids on the grounds of distinct molecular patterns. The ability of these endosomal TLR to act as PRR for viral nucleic acids seems to rely solely on the mode of access to the endolysosomal compartment in which recognition takes place. The current dogma states that self-nucleic acids do not enter the TLR-sensing compartment under normal physiological conditions. However, it is still poorly understood how dendritic cells (DC) evade activation by self-nucleic acids, in particular with regard to specific DC subsets, which are specialized in taking up material from dying cells for cross-presentation of cell-associated antigens. In this review we discuss the current understanding of how the immune system distinguishes between foreign and self-nucleic acids and point out some of the key aspects that still require further research and clarification.
    Frontiers in Cellular and Infection Microbiology 07/2013; 3:37. DOI:10.3389/fcimb.2013.00037 · 3.72 Impact Factor
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