TY  - JOUR
AU  - Khan, Nida S
AU  - Lukason, Daniel P
AU  - Feliu, Marianela
AU  - Ward, Rebecca A
AU  - Lord, Allison K
AU  - Reedy, Jennifer L
AU  - Ramirez-Ortiz, Zaida G
AU  - Tam, Jenny M
AU  - Kasperkovitz, Pia V
AU  - Negoro, Paige E
AU  - Vyas, Tammy D
AU  - Xu, Shuying
AU  - Brinkmann, Melanie M
AU  - Acharaya, Mridu
AU  - Artavanis-Tsakonas, Katerina
AU  - Frickel, Eva-Maria
AU  - Becker, Christine E
AU  - Dagher, Zeina
AU  - Kim, You-Me
AU  - Latz, Eicke
AU  - Ploegh, Hidde L
AU  - Mansour, Michael K
AU  - Miranti, Cindy K
AU  - Levitz, Stuart M
AU  - Vyas, Jatin M
TI  - CD82 controls CpG-dependent TLR9 signaling.
JO  - The FASEB journal
VL  - 33
IS  - 11
SN  - 0892-6638
CY  - Hoboken, NJ
PB  - Wiley
M1  - DZNE-2020-00423
SP  - 12500-12514
PY  - 2019
AB  - The 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.
KW  - Active Transport, Cell Nucleus: drug effects
KW  - Active Transport, Cell Nucleus: genetics
KW  - Active Transport, Cell Nucleus: immunology
KW  - Animals
KW  - Cell Nucleus: genetics
KW  - Cell Nucleus: immunology
KW  - Cytokines: genetics
KW  - Cytokines: immunology
KW  - Endoplasmic Reticulum: genetics
KW  - Endoplasmic Reticulum: immunology
KW  - Endoplasmic Reticulum: pathology
KW  - Inflammation: genetics
KW  - Inflammation: immunology
KW  - Inflammation: pathology
KW  - Kangai-1 Protein: genetics
KW  - Kangai-1 Protein: immunology
KW  - Macrophages: immunology
KW  - Macrophages: pathology
KW  - Mice
KW  - Mice, Knockout
KW  - NF-kappa B: genetics
KW  - NF-kappa B: immunology
KW  - Oligodeoxyribonucleotides: pharmacology
KW  - RAW 264.7 Cells
KW  - Signal Transduction: drug effects
KW  - Signal Transduction: genetics
KW  - Signal Transduction: immunology
KW  - Toll-Like Receptor 9: genetics
KW  - Toll-Like Receptor 9: immunology
KW  - CPG-oligonucleotide (NLM Chemicals)
KW  - Cd82 antigen, mouse (NLM Chemicals)
KW  - Cytokines (NLM Chemicals)
KW  - Kangai-1 Protein (NLM Chemicals)
KW  - NF-kappa B (NLM Chemicals)
KW  - Oligodeoxyribonucleotides (NLM Chemicals)
KW  - Tlr9 protein, mouse (NLM Chemicals)
KW  - Toll-Like Receptor 9 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:31408613
C2  - pmc:PMC6988855
DO  - DOI:10.1096/fj.201901547R
UR  - https://pub.dzne.de/record/145064
ER  -