CD82 controls CpG-dependent TLR9 signaling

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, idu Acharaya, Katerina Artavanis-Tsakonas, Eva Maria Frickel, Christine E. Becker, Zeina Dagher, You Me Kim, Eicke LatzHidde L. Ploegh, Michael K. Mansour, Cindy K. Miranti, Stuart M. Levitz, Jatin M. Vyas

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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-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.

Original languageEnglish (US)
Pages (from-to)12500-12514
Number of pages15
JournalFASEB Journal
Volume33
Issue number11
DOIs
StatePublished - Nov 1 2019
Externally publishedYes

Keywords

  • macrophages
  • myddosome
  • tetraspanins
  • TLRs

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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