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CD82 controls CpG-dependent TLR9 signaling. 2019
Nida S Khan, and
Daniel P Lukason, and
Marianela Feliu, and
Rebecca A Ward, and
Allison K Lord, and
Jennifer L Reedy, and
Zaida G Ramirez-Ortiz, and
Jenny M Tam, and
Pia V Kasperkovitz, and
Paige E Negoro, and
Tammy D Vyas, and
Shuying Xu, and
Melanie M Brinkmann, and
Mridu Acharaya, and
Katerina Artavanis-Tsakonas, and
Eva-Maria Frickel, and
Christine E Becker, and
Zeina Dagher, and
You-Me Kim, and
Eicke Latz, and
Hidde L Ploegh, and
Michael K Mansour, and
Cindy K Miranti, and
Stuart M Levitz, and
Jatin M Vyas
Division of Infectious Disease, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
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.
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Zhonghua yi xue za zhi,
