CD82 controls CpG-dependent TLR9 signaling.
journal contributionposted on 02.11.2021, 12:13 authored by Nida S Khan, Daniel P Lukason, Marianela Feliu, Rebecca A Ward, Allison K Lord, Jennifer L Reedy, Zaida G Ramirez-Ortiz, Jenny M Tam, Pia V Kasperkovitz, Paige E Negoro, Tammy D Vyas, Shuying Xu, Melanie M Brinkmann, Mridu Acharaya, Katerina Artavanis-Tsakonas, Eva-Maria Frickel, Christine E Becker, Zeina Dagher, You-Me Kim, Eicke Latz, Hidde L Ploegh, Michael K Mansour, Cindy K Miranti, Stuart M Levitz, Jatin M Vyas
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.
Crick (Grant ID: 10076, Grant title: Frickel FC001076)
macrophagesmyddosometetraspaninsTLRsActive Transport, Cell NucleusAnimalsCell NucleusCytokinesEndoplasmic ReticulumInflammationKangai-1 ProteinMacrophagesMiceMice, KnockoutNF-kappa BOligodeoxyribonucleotidesRAW 264.7 CellsSignal TransductionToll-Like Receptor 9Frickel FC001076Biochemistry & Molecular Biology0601 Biochemistry and Cell Biology0606 Physiology1116 Medical Physiology