| Autor: |
Khan NS; Division of Infectious Disease, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.; Biomedical Engineering and Biotechnology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.; Biomedical Engineering and Biotechnology, University of Massachusetts Lowell, Lowell, Massachusetts, USA.; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA., Lukason DP; Division of Infectious Disease, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA., Feliu M; Division of Infectious Disease, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA., Ward RA; Division of Infectious Disease, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA., Lord AK; Division of Infectious Disease, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA., Reedy JL; Division of Infectious Disease, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA., Ramirez-Ortiz ZG; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.; Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA., Tam JM; Division of Infectious Disease, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA., Kasperkovitz PV; F. Hoffmann-La Roche Innovation Center Basel, Basel, Switzerland., Negoro PE; Division of Infectious Disease, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA., Vyas TD; Division of Infectious Disease, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA., Xu S; Division of Infectious Disease, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA., Brinkmann MM; Viral Immune Modulation Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany.; Institute of Genetics, Technische Universität Braunschweig, Braunschweig, Germany., Acharaya M; Benaroya Research Institute, Seattle, Washington, USA.; Center for Immunity and Immunotherapy, Seattle Children's Research Institute, Seattle, Washington, USA., Artavanis-Tsakonas K; Department of Pathology, University of Cambridge, Cambridge, United Kingdom., Frickel EM; Host-Toxoplasma Interaction Laboratory, The Francis Crick Institute, London, United Kingdom., Becker CE; Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA., Dagher Z; Division of Infectious Disease, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA., Kim YM; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany., Latz E; Department of Medicine, University of Massachusetts Medical School, Boston, Massachusetts, USA.; Institute of Innate Immunity, University Hospital Bonn, University of Bonn, Bonn, Germany.; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany., Ploegh HL; Boston Children's Hospital, Boston, Massachusetts, USA., Mansour MK; Division of Infectious Disease, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA., Miranti CK; Laboratory of Integrin Signaling and Tumorigenesis, Van Andel Research Institute, Grand Rapids, Michigan, USA.; Department of Cellular and Molecular Medicine, University of Arizona Cancer Center, Tucson, Arizona, USA., Levitz SM; Department of Medicine, University of Massachusetts Medical School, Boston, Massachusetts, USA., Vyas JM; Division of Infectious Disease, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. |
| Abstrakt: |
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. |
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