| Title: |
IFITM3 restricts virus-induced inflammatory cytokine production by limiting Nogo-B mediated TLR responses. |
| Authors: |
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 |
| Source: |
essn: 2041-1723 ; nlmid: 101528555 |
| Publisher Information: |
Springer Nature; //doi.org/10.1038/s41467-022-32587-4 |
| Publication Year: |
2022 |
| Collection: |
Apollo - University of Cambridge Repository |
| Subject Terms: |
Animals; COVID-19; Cytokines; Humans; Interleukin-6; Membrane Proteins; Mice; Nogo Proteins; RNA-Binding Proteins; SARS-CoV-2; Toll-Like Receptor 2 |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
PMC9454482; https://www.repository.cam.ac.uk/handle/1810/341851 |
| DOI: |
10.17863/CAM.89275 |
| Availability: |
https://www.repository.cam.ac.uk/handle/1810/341851; https://doi.org/10.17863/CAM.89275 |
| Rights: |
Attribution 4.0 International ; https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.9266EDA7 |
| Database: |
BASE |