Interferon-induced transmembrane protein 3 (IFITM3) is a restriction factor that limits viral pathogenesis and exerts poorly understood immunoregulatory functions. Here, using human and mouse models, we demonstrate that IFITM3 promotes MyD88-dependent, TLR-mediated IL-6 production following exposure to cytomegalovirus (CMV). IFITM3 also restricts IL-6 production in response to influenza and SARS-CoV-2. In dendritic cells, IFITM3 binds to the reticulon 4 isoform Nogo-B and promotes its proteasomal degradation. We reveal that Nogo-B mediates TLR-dependent pro-inflammatory cytokine production and promotes viral pathogenesis in vivo, and in the case of TLR2 responses, this process involves alteration of TLR2 cellular localization. Nogo-B deletion abrogates inflammatory cytokine responses and associated disease in virus-infected IFITM3-deficient mice. Thus, we uncover Nogo-B as a driver of viral pathogenesis and highlight an immunoregulatory pathway in which IFITM3 fine-tunes the responsiveness of myeloid cells to viral stimulation.
Author list:
Affiliations:
- Division of Infection and Immunity/Systems Immunity University Research Institute, Cardiff University, Cardiff CF14 4XN, UK.
- MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, Oxford University, Oxford OX3 9DS, UK.
- Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK.
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
- Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK.
- Fourth Military Medical University, Xian, China.
- Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06536, USA.
- Departments of Neurology and Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA.
Authors:
M. Clement1,9, J. L. Forbester1,2,9, M. Marsden1, P. Sabberwal1, M. S. Sommerville1, D. Wellington2,3, S. Dimonte1, S. Clare4, K. Harcourt4, Z. Yin2,3, L. Nobre5, R. Antrobus5, B. Jin6, M. Chen7, S. Makvandi-Nejad2, J. A. Lindborg8, S. M. Strittmatter 8, M. P. Weekes5, R. J. Stanton1, T. Dong2,3 & I. R. Humphreys1
