Journal
NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-32587-4
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Funding
- Wellcome Trust [207503/Z/17/Z, 108070/Z/15/Z, WT098051]
- Medical Research Council, United Kingdom [MR/L018942/1]
- Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS), China [2018-I2M-2-002]
- MRC/NIHR through the UK Coronavirus Immunology Consortium (CiC) [MR/V028448/1]
- Cardiff University Systems Immunity University Research Institute PhD Studentship
- Wellcome Trust
- Medical Research Council
- NIHR/Wellcome Trust Clinical Research Facility
- Medical Research Council, United Kingdom (MRC Human Immunology Unit Core)
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IFITM3 restricts viral pathogenesis by regulating Nogo-B-mediated inflammatory response, not only in response to cytomegalovirus but also to influenza and SARS-CoV-2.
The effect of IFITM3 on viral pathogenesis is poorly understood. Here, the authors show that IFITM3 restricts cytomegalovirus pathogenesis by reducing Nogo-B-mediated inflammation in response to viral stimuli. 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.
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