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CD82 controls CpG-dependent TLR9 signaling
Nida S Khan1,2,3,4, Daniel P Lukason1, Marianela Feliu1
1Division of Infectious Disease, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
Abstract:
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.
Insights
The tetraspanin CD82 regulates Toll-like receptor 9 (TLR9) signaling, crucial for innate immunity. This study reveals CD82
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- The tetraspanin CD82 is known to suppress tumor metastasis and regulate cell processes.
- Its role in innate immunity, particularly in Toll-like receptor (TLR) signaling, remains unexplored.
Purpose of the Study:
- To investigate the function of CD82 in the innate immune response.
- To elucidate the mechanisms by which CD82 influences TLR9 trafficking and signaling.
Main Methods:
- Co-immunoprecipitation assays to detect TLR9 and CD82 association in macrophages.
- Confocal microscopy to visualize TLR9 and CD82 localization.
- Analysis of myddosome formation and NF-κB nuclear translocation in response to CpG stimulation.
Main Results:
- CD82 and TLR9 were found to associate in macrophages within the endoplasmic reticulum and post-ER compartments.
- CD82 is essential for the formation of the myddosome complex upon CpG stimulation.
- CD82 modulates TLR9-dependent NF-κB activation, impacting inflammatory cytokine production.
Conclusions:
- CD82 is a key regulator of TLR9 trafficking and signaling pathways.
- This finding represents the first implication of a tetraspanin in TLR signaling regulation.
- CD82's role in TLR9 signaling has potential implications for cancer immunotherapy and host defense against pathogens.
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