CD82 controls CpG‐dependent TLR9 signaling

• Published in: The FASEB journal Vol. 33; no. 11; pp. 12500 - 12514
• Main Authors: Khan, Nida S., Lukason, Daniel P., Feliu, Marianela, Ward, Rebecca A., Lord, Allison K., Reedy, Jennifer L., Ramirez‐Ortiz, Zaida G., Tam, Jenny M., Kasperkovitz, Pia V., Negoro, Paige E., Vyas, Tammy D., Xu, Shuying, Brinkmann, Melanie M., Acharaya, idu, Artavanis‐Tsakonas, Katerina, Frickel, Eva‐Maria, Becker, Christine E., Dagher, Zeina, Kim, You‐Me, Latz, Eicke, Ploegh, Hidde L., Mansour, Michael K., Miranti, Cindy K., Levitz, Stuart M., Vyas, Jatin M.
• Format: Journal Article
• Language: English
• Published: United States Federation of American Societies for Experimental Biology 01-11-2019
• Subjects: Active Transport, Cell Nucleus - drug effects; Active Transport, Cell Nucleus - genetics; Active Transport, Cell Nucleus - immunology; Animals; Cell Nucleus - genetics; Cell Nucleus - immunology; Cytokines - genetics; Cytokines - immunology; Endoplasmic Reticulum - genetics; Endoplasmic Reticulum - immunology; Endoplasmic Reticulum - pathology; Inflammation - genetics; Inflammation - immunology; Inflammation - pathology; Kangai-1 Protein - genetics; Kangai-1 Protein - immunology; macrophages; Macrophages - immunology; Macrophages - pathology; Mice; Mice, Knockout; myddosome; NF-kappa B - genetics; NF-kappa B - immunology; Oligodeoxyribonucleotides - pharmacology; RAW 264.7 Cells; Signal Transduction - drug effects; Signal Transduction - genetics; Signal Transduction - immunology; tetraspanins; TLRs; Toll-Like Receptor 9 - genetics; Toll-Like Receptor 9 - immunology; myddosome; tetraspanins; macrophages; TLRs
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.201901547R

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‐αB 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. FASEB J. 33, 12500–12514 (2019). www.fasebj.org