Nat Commun
. 2022 Sep 8;13(1):5294.
doi: 10.1038/s41467-022-32587-4.
IFITM3 restricts virus-induced inflammatory cytokine production by limiting Nogo-B mediated TLR responses
M Clement # 1 , J L Forbester # 1 2 , M Marsden 1 , P Sabberwal 1 , M S Sommerville 1 , D Wellington 2 3 , S Dimonte 1 , S Clare 4 , K Harcourt 4 , Z Yin 2 3 , L Nobre 5 , R Antrobus 5 , B Jin 6 , M Chen 7 , S Makvandi-Nejad 2 , J A Lindborg 8 , S M Strittmatter 8 , M P Weekes 5 , R J Stanton 1 , T Dong 2 3 , I R Humphreys 9
Affiliations
- PMID: 36075894
- DOI: 10.1038/s41467-022-32587-4
Abstract
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.