000145064 001__ 145064 000145064 005__ 20250415100044.0 000145064 0247_ $$2doi$$a10.1096/fj.201901547R 000145064 0247_ $$2pmid$$apmid:31408613 000145064 0247_ $$2pmc$$apmc:PMC6988855 000145064 0247_ $$2ISSN$$a0892-6638 000145064 0247_ $$2ISSN$$a1530-6860 000145064 0247_ $$2altmetric$$aaltmetric:64959782 000145064 037__ $$aDZNE-2020-00423 000145064 041__ $$aEnglish 000145064 082__ $$a570 000145064 1001_ $$aKhan, Nida S$$b0 000145064 245__ $$aCD82 controls CpG-dependent TLR9 signaling. 000145064 260__ $$aHoboken, NJ$$bWiley$$c2019 000145064 264_1 $$2Crossref$$3online$$bWiley$$c2019-08-13 000145064 264_1 $$2Crossref$$3print$$bWiley$$c2019-11-01 000145064 3367_ $$2DRIVER$$aarticle 000145064 3367_ $$2DataCite$$aOutput Types/Journal article 000145064 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1744701697_3428 000145064 3367_ $$2BibTeX$$aARTICLE 000145064 3367_ $$2ORCID$$aJOURNAL_ARTICLE 000145064 3367_ $$00$$2EndNote$$aJournal Article 000145064 520__ $$aThe tetraspanin CD82 is a potent suppressor of tumor metastasis and regulates several processes including signal transduction, cell adhesion, motility, and aggregation. However, the mechanisms by which CD82 participates in innate immunity are unknown. We report that CD82 is a key regulator of TLR9 trafficking and signaling. TLR9 recognizes unmethylated cytosine-phosphate-guanine (CpG) motifs present in viral, bacterial, and fungal DNA. We demonstrate that TLR9 and CD82 associate in macrophages, which occurs in the endoplasmic reticulum (ER) and post-ER. Moreover, CD82 is essential for TLR9-dependent myddosome formation in response to CpG stimulation. Finally, CD82 modulates TLR9-dependent NF-κB nuclear translocation, which is critical for inflammatory cytokine production. To our knowledge, this is the first time a tetraspanin has been implicated as a key regulator of TLR signaling. Collectively, our study demonstrates that CD82 is a specific regulator of TLR9 signaling, which may be critical in cancer immunotherapy approaches and coordinating the innate immune response to pathogens. 000145064 536__ $$0G:(DE-HGF)POF3-342$$a342 - Disease Mechanisms and Model Systems (POF3-342)$$cPOF3-342$$fPOF III$$x0 000145064 542__ $$2Crossref$$i2019-08-13$$uhttp://onlinelibrary.wiley.com/termsAndConditions#vor 000145064 542__ $$2Crossref$$i2019-08-13$$uhttp://doi.wiley.com/10.1002/tdm_license_1.1 000145064 588__ $$aDataset connected to CrossRef, PubMed, 000145064 650_7 $$2NLM Chemicals$$aCPG-oligonucleotide 000145064 650_7 $$2NLM Chemicals$$aCd82 antigen, mouse 000145064 650_7 $$2NLM Chemicals$$aCytokines 000145064 650_7 $$2NLM Chemicals$$aKangai-1 Protein 000145064 650_7 $$2NLM Chemicals$$aNF-kappa B 000145064 650_7 $$2NLM Chemicals$$aOligodeoxyribonucleotides 000145064 650_7 $$2NLM Chemicals$$aTlr9 protein, mouse 000145064 650_7 $$2NLM Chemicals$$aToll-Like Receptor 9 000145064 650_2 $$2MeSH$$aActive Transport, Cell Nucleus: drug effects 000145064 650_2 $$2MeSH$$aActive Transport, Cell Nucleus: genetics 000145064 650_2 $$2MeSH$$aActive Transport, Cell Nucleus: immunology 000145064 650_2 $$2MeSH$$aAnimals 000145064 650_2 $$2MeSH$$aCell Nucleus: genetics 000145064 650_2 $$2MeSH$$aCell Nucleus: immunology 000145064 650_2 $$2MeSH$$aCytokines: genetics 000145064 650_2 $$2MeSH$$aCytokines: immunology 000145064 650_2 $$2MeSH$$aEndoplasmic Reticulum: genetics 000145064 650_2 $$2MeSH$$aEndoplasmic Reticulum: immunology 000145064 650_2 $$2MeSH$$aEndoplasmic Reticulum: pathology 000145064 650_2 $$2MeSH$$aInflammation: genetics 000145064 650_2 $$2MeSH$$aInflammation: immunology 000145064 650_2 $$2MeSH$$aInflammation: pathology 000145064 650_2 $$2MeSH$$aKangai-1 Protein: genetics 000145064 650_2 $$2MeSH$$aKangai-1 Protein: immunology 000145064 650_2 $$2MeSH$$aMacrophages: immunology 000145064 650_2 $$2MeSH$$aMacrophages: pathology 000145064 650_2 $$2MeSH$$aMice 000145064 650_2 $$2MeSH$$aMice, Knockout 000145064 650_2 $$2MeSH$$aNF-kappa B: genetics 000145064 650_2 $$2MeSH$$aNF-kappa B: immunology 000145064 650_2 $$2MeSH$$aOligodeoxyribonucleotides: pharmacology 000145064 650_2 $$2MeSH$$aRAW 264.7 Cells 000145064 650_2 $$2MeSH$$aSignal Transduction: drug effects 000145064 650_2 $$2MeSH$$aSignal Transduction: genetics 000145064 650_2 $$2MeSH$$aSignal Transduction: immunology 000145064 650_2 $$2MeSH$$aToll-Like Receptor 9: genetics 000145064 650_2 $$2MeSH$$aToll-Like Receptor 9: immunology 000145064 7001_ $$aLukason, Daniel P$$b1 000145064 7001_ $$aFeliu, Marianela$$b2 000145064 7001_ $$aWard, Rebecca A$$b3 000145064 7001_ $$aLord, Allison K$$b4 000145064 7001_ $$aReedy, Jennifer L$$b5 000145064 7001_ $$aRamirez-Ortiz, Zaida G$$b6 000145064 7001_ $$aTam, Jenny M$$b7 000145064 7001_ $$aKasperkovitz, Pia V$$b8 000145064 7001_ $$aNegoro, Paige E$$b9 000145064 7001_ $$aVyas, Tammy D$$b10 000145064 7001_ $$aXu, Shuying$$b11 000145064 7001_ $$aBrinkmann, Melanie M$$b12 000145064 7001_ $$aAcharaya, Mridu$$b13 000145064 7001_ $$aArtavanis-Tsakonas, Katerina$$b14 000145064 7001_ $$aFrickel, Eva-Maria$$b15 000145064 7001_ $$aBecker, Christine E$$b16 000145064 7001_ $$aDagher, Zeina$$b17 000145064 7001_ $$0P:(DE-HGF)0$$aKim, You-Me$$b18 000145064 7001_ $$0P:(DE-2719)2000062$$aLatz, Eicke$$b19 000145064 7001_ $$aPloegh, Hidde L$$b20 000145064 7001_ $$aMansour, Michael K$$b21 000145064 7001_ $$aMiranti, Cindy K$$b22 000145064 7001_ $$aLevitz, Stuart M$$b23 000145064 7001_ $$0P:(DE-HGF)0$$aVyas, Jatin M$$b24$$eCorresponding author 000145064 77318 $$2Crossref$$3journal-article$$a10.1096/fj.201901547r$$b : Wiley, 2019-08-13$$n11$$p12500-12514$$tThe FASEB Journal$$v33$$x0892-6638$$y2019 000145064 773__ $$0PERI:(DE-600)1468876-1$$a10.1096/fj.201901547R$$gVol. 33, no. 11, p. 12500 - 12514$$n11$$p12500-12514$$tThe FASEB journal$$v33$$x0892-6638$$y2019 000145064 8564_ 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999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1038/ni.1636$$o10.1038/ni.1636 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1073/pnas.1518976113$$o10.1073/pnas.1518976113 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/S0306-3623(97)00434-5$$o10.1016/S0306-3623(97)00434-5 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1038/srep44042$$o10.1038/srep44042 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.3389/fimmu.2018.01491$$o10.3389/fimmu.2018.01491 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1242/jcs.088047$$o10.1242/jcs.088047 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.molmed.2007.09.002$$o10.1016/j.molmed.2007.09.002 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1038/nri1548$$o10.1038/nri1548 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.4049/jimmunol.0802797$$o10.4049/jimmunol.0802797 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1002/eji.1830270712$$o10.1002/eji.1830270712 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1074/jbc.M601337200$$o10.1074/jbc.M601337200 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.4049/jimmunol.178.1.154$$o10.4049/jimmunol.178.1.154 000145064 999C5 $$2Crossref$$oKoh H. J. 2018$$y2018 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1038/ni1297$$o10.1038/ni1297 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.immuni.2009.09.013$$o10.1016/j.immuni.2009.09.013 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1242/jcs.062497$$o10.1242/jcs.062497 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1371/journal.ppat.1003873$$o10.1371/journal.ppat.1003873 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1038/nature10071$$o10.1038/nature10071 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1084/jem.20021890$$o10.1084/jem.20021890 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1084/jem.20021787$$o10.1084/jem.20021787 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.4161/auto.29411$$o10.4161/auto.29411 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.cell.2019.01.039$$o10.1016/j.cell.2019.01.039 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1038/nri3757$$o10.1038/nri3757 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.15252/emmm.201404556$$o10.15252/emmm.201404556 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1002/jlb.57.6.956$$o10.1002/jlb.57.6.956 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.jns.2016.12.027$$o10.1016/j.jns.2016.12.027 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1128/CDLI.4.2.229-231.1997$$o10.1128/CDLI.4.2.229-231.1997 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1172/JCI39748$$o10.1172/JCI39748 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1158/0008-5472.CAN-06-0206$$o10.1158/0008-5472.CAN-06-0206 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.uct.2007.11.003$$o10.1016/j.uct.2007.11.003 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.4049/jimmunol.167.1.66$$o10.4049/jimmunol.167.1.66 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1371/journal.pone.0051797$$o10.1371/journal.pone.0051797 000145064 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1038/nm1444$$o10.1038/nm1444