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FASEB J. 2019 Nov;33(11):12500-12514. doi: 10.1096/fj.201901547R. Epub 2019 Aug 13.

CD82 controls CpG-dependent TLR9 signaling.

Author information

1
Division of Infectious Disease, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
2
Biomedical Engineering and Biotechnology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
3
Biomedical Engineering and Biotechnology, University of Massachusetts Lowell, Lowell, Massachusetts, USA.
4
Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
5
Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
6
Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
7
F. Hoffmann-La Roche Innovation Center Basel, Basel, Switzerland.
8
Viral Immune Modulation Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.
9
Institute of Genetics, Technische Universit├Ąt Braunschweig, Braunschweig, Germany.
10
Benaroya Research Institute, Seattle, Washington, USA.
11
Center for Immunity and Immunotherapy, Seattle Children's Research Institute, Seattle, Washington, USA.
12
Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
13
Host-Toxoplasma Interaction Laboratory, The Francis Crick Institute, London, United Kingdom.
14
Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
15
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
16
Department of Medicine, University of Massachusetts Medical School, Boston, Massachusetts, USA.
17
Institute of Innate Immunity, University Hospital Bonn, University of Bonn, Bonn, Germany.
18
Boston Children's Hospital, Boston, Massachusetts, USA.
19
Laboratory of Integrin Signaling and Tumorigenesis, Van Andel Research Institute, Grand Rapids, Michigan, USA.
20
Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, Tucson, Arizona, 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-╬║B 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.

KEYWORDS:

TLRs; macrophages; myddosome; tetraspanins

PMID:
31408613
DOI:
10.1096/fj.201901547R

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