IFITM3 restricts virus-induced inflammatory cytokine production by limiting Nogo-B mediated TLR responses.
Clement M., Forbester JL., Marsden M., Sabberwal P., Sommerville MS., Wellington D., Dimonte S., Clare S., Harcourt K., Yin Z., Nobre L., Antrobus R., Jin B., Chen M., Makvandi-Nejad S., Lindborg JA., Strittmatter SM., Weekes MP., Stanton RJ., Dong T., Humphreys IR.
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.