IFITM3 restricts virus-induced inflammatory cytokine production by limiting Nogo-B mediated TLR responses


Nature Communications

Contributing to research themes:

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:


  1. Division of Infection and Immunity/Systems Immunity University Research Institute, Cardiff University, Cardiff CF14 4XN, UK. 
  2. MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, Oxford University, Oxford OX3 9DS, UK. 
  3. Chinese Academy of Medical Sciences (CAMS) Oxford Institute (COI), University of Oxford, Oxford, UK. 
  4. Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. 
  5. Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK. 
  6. Fourth Military Medical University, Xian, China. 
  7. Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06536, USA. 
  8. Departments of Neurology and Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA.


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