FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2012473400> ?p ?o ?g. }

• W2012473400 endingPage "5" @default.
• W2012473400 startingPage "3" @default.
• W2012473400 abstract "Unc93B1, a multitransmembrane ER-resident protein, controls intracellular trafficking of endosomal Toll-like receptors. In this issue of Immunity, Fukui et al., 2011Fukui R. Saitoh S.-I. Kanno A. Onji M. Shibata T. Ito A. Onji M. Matsumoto M. Akira S. Yoshida N. Miyake K. Immunity. 2011; 35 (this issue): 69-81Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar revealed that Unc93B1 regulates differential transport of TLR7 and TLR9 into signaling endosomes to prevent autoimmunity. Unc93B1, a multitransmembrane ER-resident protein, controls intracellular trafficking of endosomal Toll-like receptors. In this issue of Immunity, Fukui et al., 2011Fukui R. Saitoh S.-I. Kanno A. Onji M. Shibata T. Ito A. Onji M. Matsumoto M. Akira S. Yoshida N. Miyake K. Immunity. 2011; 35 (this issue): 69-81Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar revealed that Unc93B1 regulates differential transport of TLR7 and TLR9 into signaling endosomes to prevent autoimmunity. Endosomal Toll-like receptors (TLRs) recognize viral nucleic acids and induce activation of antiviral genes. Upon endocytosis of virions, TLR9 binds to double-stranded DNA (dsDNA) rich in unmethylated CpG motifs found in DNA viruses, and TLR7 recognizes single-stranded RNA (ssRNA) with GU-rich sequences found in viral RNA. However, such molecular patterns associated with viral nucleic acids are not necessarily unique to viruses, because mammalian nucleic acids also share features that are recognized by these TLRs. Under certain circumstances, self nucleic acids can accidentally enter the endosome and trigger TLR7 and TLR9, which can lead to autoimmune diseases including psoriasis, arthritis, and systemic lupus erythematosus (SLE) (Marshak-Rothstein and Rifkin, 2007Marshak-Rothstein A. Rifkin I.R. Annu. Rev. Immunol. 2007; 25: 419-441Crossref PubMed Scopus (299) Google Scholar). The innate immune system has in place multiple regulatory mechanisms to prevent recognition of self nucleic acids. One such mechanism involves regulation of TLR intracellular trafficking. At steady state, the majority of TLR7 and TLR9 are expressed in the endoplasmic reticulum (ER) (Figure 1). Upon viral infection or TLR signaling, TLR7 and TLR9 are mobilized to traffic from the ER to the endosomes where viral recognition takes place. A multitransmembrane protein found in the ER at steady state, Unc93B1, controls trafficking of all endosomal TLRs, TLR3, 7, 8, and 9 (Kim et al., 2008Kim Y.M. Brinkmann M.M. Paquet M.E. Ploegh H.L. Nature. 2008; 452: 234-238Crossref PubMed Scopus (491) Google Scholar). Subcellular localization of TLR7 and TLR9 is regulated such that these receptors are confined to the endosomes and are excluded from the plasma membrane, where self nucleic acids are accessible. An additional level of control is provided by the fact that TLR7 and TLR9 are active only once they are cleaved in the acidified “signaling endosomes” by endosomal proteases (Figure 1; Barton and Kagan, 2009Barton G.M. Kagan J.C. Nat. Rev. Immunol. 2009; 9: 535-542Crossref PubMed Scopus (480) Google Scholar). Once within the signaling endosomal compartment, TLR9 and TLR7 recruit the adaptor protein MyD88 and trigger signals leading to inflammatory cytokine expression through NF-κB activation. These receptors are further transported to lysosome-related organelle by the adaptor protein-3 (AP-3) complex, enabling them to recruit interferon regulatory factor-7 (IRF7) and activate transcription of type I interferon (IFN) genes (Sasai et al., 2010Sasai M. Linehan M.M. Iwasaki A. Science. 2010; 329: 1530-1534Crossref PubMed Scopus (250) Google Scholar). However, how the relative distribution of TLR7 and TLR9 in the signaling endosomes within the same responding cell is coordinated has remained unclear. The current study by Fukui et al., 2011Fukui R. Saitoh S.-I. Kanno A. Onji M. Shibata T. Ito A. Onji M. Matsumoto M. Akira S. Yoshida N. Miyake K. Immunity. 2011; 35 (this issue): 69-81Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar builds on their previous finding that TLR9 competes with TLR7 for Unc93B1-dependent transportation to signaling endosomes (Fukui et al., 2009Fukui R. Saitoh S. Matsumoto F. Kozuka-Hata H. Oyama M. Tabeta K. Beutler B. Miyake K. J. Exp. Med. 2009; 206: 1339-1350Crossref PubMed Scopus (135) Google Scholar) and reports an exuberant systemic inflammation that results from a dysregulation of this process in vivo. Previously, the same group used complementation cloning with a TLR7-unresponsive cell line and found that amino acid D34 in Unc93B1 repressed TLR7-mediated responses. Cells expressing D34A mutant Unc93B1 are hyperresponsive to TLR7 ligands but hyporesponsive to TLR9 ligands, because of preferential binding and trafficking of TLR7 into signaling endosomes (Figure 1; Fukui et al., 2009Fukui R. Saitoh S. Matsumoto F. Kozuka-Hata H. Oyama M. Tabeta K. Beutler B. Miyake K. J. Exp. Med. 2009; 206: 1339-1350Crossref PubMed Scopus (135) Google Scholar). In the current study, the authors generated genetically targeted mice harboring a D34A mutation in Unc93B1. Remarkably, these mice developed severe lethal inflammatory disease. In the absence of any other autoimmune-predisposing mutations, half of the D34A homozygous genetically targeted mice died before 30 weeks of age because of liver necrosis, with no obvious necrosis in other organs including kidney, lung, heart, and spleen. D34A mutant mice developed progressive splenomegaly with massive expansion of erythroblasts and myeloid cells, as well as severe thrombocytopenia. Moreover, autoantibody production was detected in some of these mice. To probe the pathogenesis, D34A genetically targeted mice were crossed to a variety of genetically ablated mice. TLR7 and MyD88 deficiency completely prevented disease development in D34A mice, whereas TLR9 deficiency only partially reversed the inflammatory phenotype. D34A genetically targeted mice spontaneously developed Th1 and Th17 cell responses, which were abrogated by TLR7 deficiency. Lymphocytes were required for the disease observed in D34A mice, because the D34A mutation on a Rag2−/− background completely eliminated inflammatory disease. Strikingly, B cells were required for the pathogenesis in D34A mice, as indicated by the fact that D34A mice crossed onto the B cell-deficient Ighm−/− background did not suffer from inflammatory disease and lacked spontaneous activation of Th17 cell responses. Because antibody is not required for autoreactive T cell activation in MRL/lpr mice (Chan et al., 1999Chan O.T. Hannum L.G. Haberman A.M. Madaio M.P. Shlomchik M.J. J. Exp. Med. 1999; 189: 1639-1648Crossref PubMed Scopus (572) Google Scholar) and because only a mild increase in IgG2a and IgG2b amounts were observed in D34A genetically targeted mice (Fukui et al., 2011Fukui R. Saitoh S.-I. Kanno A. Onji M. Shibata T. Ito A. Onji M. Matsumoto M. Akira S. Yoshida N. Miyake K. Immunity. 2011; 35 (this issue): 69-81Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar), the pathogenic role of B cells probably stems from their capacity to present autoantigens to T cells. Intracellular distribution analysis of TLRs in D34A genetically targeted mice revealed that, whereas TLR9 remained excluded from lysosomal-associated membrane protein-1 (LAMP1)+ compartment, TLR7 was confined almost exclusively to the LAMP1+ compartment in bone marrow-derived DCs, even in the absence of any external stimulus. These data indicate that the D34A mutant Unc93B1 not only enables preferential trafficking of TLR7 to the endosome but also overrides the requirement for TLR priming for such delivery (Figure 1). This could at least in part explain the severe autoimmune phenotype seen in D34A genetically targeted mice. On the scale of autoimmune diseases, D34A genetically targeted mice rate at the severe end—as pathogenic as in TLR7 transgenic mice carrying 8–16 extra copies of the TLR7 gene, which also develop splenomegaly, thrombocytopenia, liver inflammation, and death (Deane et al., 2007Deane J.A. Pisitkun P. Barrett R.S. Feigenbaum L. Town T. Ward J.M. Flavell R.A. Bolland S. Immunity. 2007; 27: 801-810Abstract Full Text Full Text PDF PubMed Scopus (373) Google Scholar). Even though TLR expression was unaltered in these mice, pathology in the D34A mutant mice was far beyond the SLE-like diseases seen in the Y-linked autoimmune accelerating (Yaa) model with TLR7 gene duplication, or MRL/lpr mice. These results indicate that not only the dosage, but also the subcellular location of TLR7, is strictly regulated to avoid autoimmune disease, in this case, by Unc93B1. An obvious question that arises from these findings reported here (Fukui et al., 2011Fukui R. Saitoh S.-I. Kanno A. Onji M. Shibata T. Ito A. Onji M. Matsumoto M. Akira S. Yoshida N. Miyake K. Immunity. 2011; 35 (this issue): 69-81Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar) is why TLR7, but not TLR9, stimulation results in autoimmune outcomes. This dichotomy is even more exaggerated in the case of autoimmune-prone MRL/lpr mice, where TLR9 ameliorates disease progression (Christensen et al., 2006Christensen S.R. Shupe J. Nickerson K. Kashgarian M. Flavell R.A. Shlomchik M.J. Immunity. 2006; 25: 417-428Abstract Full Text Full Text PDF PubMed Scopus (752) Google Scholar) and the protective role for TLR9 depends on its antagonism of TLR7 (Nickerson et al., 2010Nickerson K.M. Christensen S.R. Shupe J. Kashgarian M. Kim D. Elkon K. Shlomchik M.J. J. Immunol. 2010; 184: 1840-1848Crossref PubMed Scopus (233) Google Scholar). First, although downstream signaling is assumed to be the same between TLR7 and TLR9, this has not been formally tested. If TLR7 and TLR9 can form heterodimers, downstream signaling can be regulated by the ratio of homo- versus heterodimers. Second, it is possible that endogenous TLR7 ligands are more abundant and/or potent in inducing signals compared to TLR9 ligands. Third, it is also possible to imagine a scenario in which two separate cell types are involved—e.g., cells expressing TLR7 selectively induce transcription program that leads to overt inflammation in contrast to those expressing TLR9. However, the current study highlights that within the same responding cell, competition over Unc93B1 binding by TLR7 and TLR9 can have a profound consequence after recognition of endogenous nucleic acids. These results also provide a platform with which to investigate the endogenous ligands responsible for activating TLR7 and the cell types responsible for pathogenesis of various autoimmune diseases. The pathogenic role of B cells in this regard is particularly interesting, and future studies are needed to probe whether cell-intrinsic or -extrinsic requirements for B cell TLR signaling leads to autoimmune T cell activation. In addition to B cells, involvement of plasmacytoid dendritic cells, dendritic cells, and macrophages that also express these TLRs needs to be clarified. Even though the D34A mutation is not known to occur naturally in humans, whether other single-nucleotide polymorphisms (SNPs) within the Unc93b1 gene or those that affect TLR trafficking in general are associated with autoimmune diseases in humans remains an intriguing question for future studies. Finally, an evolutionarily relevant question that emerges from these findings is why viral-sensing TLRs and not bacterial TLR sensors need be coregulated. Bacterial pathogen-associated molecular patterns (PAMPs) have unique molecular signatures that are absent from mammalian cells, and TLRs that recognize these do not require an additional level of regulation among the receptors. In contrast, viral PAMPs are shared by endogenous nucleic acids and require an additional level of regulation. Such coregulation of TLR7 and TLR9 may have evolved to be optimized to avoid stimulation when they collectively sense the relative abundance of RNA to DNA from endogenous sources (i.e., dead cells) but can still engage robust activation when RNA or DNA predominates during a virus infection. In this regard, D34A mutant Unc93B1 also preferentially binds TLR8 and TLR13 compared to WT Unc93B1 (Fukui et al., 2009Fukui R. Saitoh S. Matsumoto F. Kozuka-Hata H. Oyama M. Tabeta K. Beutler B. Miyake K. J. Exp. Med. 2009; 206: 1339-1350Crossref PubMed Scopus (135) Google Scholar), indicating that coregulated trafficking by Unc93B1 extends to RNA (TLR7, TLR8, and potentially TLR13) versus DNA (TLR9) sensing TLRs. Therefore, the love triangle between Unc93B1, TLR7, and TLR9 may indeed involve more partners and much remains to be seen how attraction between these nucleic acid-sensing TLRs play out in keeping us out of fatal attraction. Unc93B1 Restricts Systemic Lethal Inflammation by Orchestrating Toll-like Receptor 7 and 9 TraffickingFukui et al.ImmunityJune 16, 2011In BriefToll-like receptor-7 (TLR7) and 9, innate immune sensors for microbial RNA or DNA, have been implicated in autoimmunity. Upon activation, TLR7 and 9 are transported from the endoplasmic reticulum (ER) to endolysosomes for nucleic acid sensing by an ER-resident protein, Unc93B1. Little is known, however, about a role for sensor transportation in controlling autoimmunity. TLR9 competes with TLR7 for Unc93B1-dependent trafficking and predominates over TLR7. TLR9 skewing is actively maintained by Unc93B1 and reversed to TLR7 if Unc93B1 loses preferential binding via a D34A mutation. Full-Text PDF Open Archive" @default.
• W2012473400 created "2016-06-24" @default.
• W2012473400 creator A5010263068 @default.
• W2012473400 creator A5042204828 @default.
• W2012473400 date "2011-07-01" @default.
• W2012473400 modified "2023-10-18" @default.
• W2012473400 title "Love Triangle between Unc93B1, TLR7, and TLR9 Prevents Fatal Attraction" @default.
• W2012473400 cites W1969354039 @default.
• W2012473400 cites W1997977259 @default.
• W2012473400 cites W2021257197 @default.
• W2012473400 cites W2042732565 @default.
• W2012473400 cites W2043948229 @default.
• W2012473400 cites W2061203855 @default.
• W2012473400 cites W2129359803 @default.
• W2012473400 cites W2134106169 @default.
• W2012473400 cites W2143642734 @default.
• W2012473400 cites W2164865997 @default.
• W2012473400 doi "https://doi.org/10.1016/j.immuni.2011.07.006" @default.
• W2012473400 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3143494" @default.
• W2012473400 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/21777792" @default.
• W2012473400 hasPublicationYear "2011" @default.
• W2012473400 type Work @default.
• W2012473400 sameAs 2012473400 @default.
• W2012473400 citedByCount "10" @default.
• W2012473400 countsByYear W20124734002013 @default.
• W2012473400 countsByYear W20124734002015 @default.
• W2012473400 countsByYear W20124734002017 @default.
• W2012473400 countsByYear W20124734002018 @default.
• W2012473400 countsByYear W20124734002022 @default.
• W2012473400 crossrefType "journal-article" @default.
• W2012473400 hasAuthorship W2012473400A5010263068 @default.
• W2012473400 hasAuthorship W2012473400A5042204828 @default.
• W2012473400 hasBestOaLocation W20124734001 @default.
• W2012473400 hasConcept C104317684 @default.
• W2012473400 hasConcept C136449434 @default.
• W2012473400 hasConcept C138885662 @default.
• W2012473400 hasConcept C150194340 @default.
• W2012473400 hasConcept C159047783 @default.
• W2012473400 hasConcept C170493617 @default.
• W2012473400 hasConcept C190727270 @default.
• W2012473400 hasConcept C2776709828 @default.
• W2012473400 hasConcept C2778364177 @default.
• W2012473400 hasConcept C2779138994 @default.
• W2012473400 hasConcept C2779836521 @default.
• W2012473400 hasConcept C41895202 @default.
• W2012473400 hasConcept C54355233 @default.
• W2012473400 hasConcept C86803240 @default.
• W2012473400 hasConcept C95444343 @default.
• W2012473400 hasConceptScore W2012473400C104317684 @default.
• W2012473400 hasConceptScore W2012473400C136449434 @default.
• W2012473400 hasConceptScore W2012473400C138885662 @default.
• W2012473400 hasConceptScore W2012473400C150194340 @default.
• W2012473400 hasConceptScore W2012473400C159047783 @default.
• W2012473400 hasConceptScore W2012473400C170493617 @default.
• W2012473400 hasConceptScore W2012473400C190727270 @default.
• W2012473400 hasConceptScore W2012473400C2776709828 @default.
• W2012473400 hasConceptScore W2012473400C2778364177 @default.
• W2012473400 hasConceptScore W2012473400C2779138994 @default.
• W2012473400 hasConceptScore W2012473400C2779836521 @default.
• W2012473400 hasConceptScore W2012473400C41895202 @default.
• W2012473400 hasConceptScore W2012473400C54355233 @default.
• W2012473400 hasConceptScore W2012473400C86803240 @default.
• W2012473400 hasConceptScore W2012473400C95444343 @default.
• W2012473400 hasIssue "1" @default.
• W2012473400 hasLocation W20124734001 @default.
• W2012473400 hasLocation W20124734002 @default.
• W2012473400 hasLocation W20124734003 @default.
• W2012473400 hasLocation W20124734004 @default.
• W2012473400 hasOpenAccess W2012473400 @default.
• W2012473400 hasPrimaryLocation W20124734001 @default.
• W2012473400 hasRelatedWork W124367702 @default.
• W2012473400 hasRelatedWork W1588911958 @default.
• W2012473400 hasRelatedWork W1964133468 @default.
• W2012473400 hasRelatedWork W2109379806 @default.
• W2012473400 hasRelatedWork W2122057816 @default.
• W2012473400 hasRelatedWork W2143642734 @default.
• W2012473400 hasRelatedWork W2146960589 @default.
• W2012473400 hasRelatedWork W2938746831 @default.
• W2012473400 hasRelatedWork W4256208549 @default.
• W2012473400 hasRelatedWork W4296841011 @default.
• W2012473400 hasVolume "35" @default.
• W2012473400 isParatext "false" @default.
• W2012473400 isRetracted "false" @default.
• W2012473400 magId "2012473400" @default.
• W2012473400 workType "article" @default.