1. IFITM3 restricts virus-induced inflammatory cytokine production by limiting Nogo-B mediated TLR responses
- Author
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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, Clement, M [0000-0002-9280-5281], Wellington, D [0000-0002-9277-0306], Yin, Z [0000-0002-2044-5838], Strittmatter, SM [0000-0001-8188-3092], Weekes, MP [0000-0003-3196-5545], Stanton, RJ [0000-0002-6799-1182], Humphreys, IR [0000-0002-9512-5337], and Apollo - University of Cambridge Repository
- Subjects
Multidisciplinary ,Interleukin-6 ,SARS-CoV-2 ,Nogo Proteins ,631/250/255/2514 ,article ,COVID-19 ,Membrane Proteins ,RNA-Binding Proteins ,General Physics and Astronomy ,631/250/262 ,13/106 ,General Chemistry ,631/250/254 ,13 ,14 ,Toll-Like Receptor 2 ,General Biochemistry, Genetics and Molecular Biology ,Mice ,13/21 ,13/51 ,14/63 ,Animals ,Cytokines ,Humans - 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.
- Published
- 2022