CD82 controls CpG-dependent TLR9 signaling.
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.-Khan, N. S., Lukason, D. P., Feliu, M., Ward, R. A., Lord, A. K., Reedy, J. L., Ramirez-Ortiz, Z. G., Tam, J. M., Kasperkovitz, P. V., Negoro, P. E., Vyas, T. D., Xu, S., Brinkmann, M. M., Acharaya, M., Artavanis-Tsakonas, K., Frickel, E.-M., Becker, C. E., Dagher, Z., Kim, Y.-M., Latz, E., Ploegh, H. L., Mansour, M. K., Miranti, C. K., Levitz, S. M., Vyas, J. M. CD82 controls CpG-dependent TLR9 signaling.
['Khan|Nida S|NS|', 'Lukason|Daniel P|DP|', 'Feliu|Marianela|M|', 'Ward|Rebecca A|RA|', 'Lord|Allison K|AK|', 'Reedy|Jennifer L|JL|', 'Ramirez-Ortiz|Zaida G|ZG|', 'Tam|Jenny M|JM|', 'Kasperkovitz|Pia V|PV|', 'Negoro|Paige E|PE|', 'Vyas|Tammy D|TD|', 'Xu|Shuying|S|', 'Brinkmann|Melanie M|MM|', 'Acharaya|Mridu|M|', 'Artavanis-Tsakonas|Katerina|K|', 'Frickel|Eva-Maria|EM|', 'Becker|Christine E|CE|', 'Dagher|Zeina|Z|', 'Kim|You-Me|YM|', 'Latz|Eicke|E|', 'Ploegh|Hidde L|HL|', 'Mansour|Michael K|MK|', 'Miranti|Cindy K|CK|', 'Levitz|Stuart M|SM|', 'Vyas|Jatin M|JM|']
D021581:Active Transport, Cell Nucleus D000818:Animals D002467:Cell Nucleus D016207:Cytokines D004721:Endoplasmic Reticulum D007249:Inflammation D051861:Kangai-1 Protein D008264:Macrophages D051379:Mice D018345:Mice, Knockout D016328:NF-kappa B D009838:Oligodeoxyribonucleotides D000067996:RAW 264.7 Cells D015398:Signal Transduction D051217:Toll-Like Receptor 9
tetraspanins macrophages myddosome TLRs