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IFITM3 regulates virus-induced inflammatory cytokine production by titrating Nogo-B orchestration of TLR responses

Clement, Mathew, Forbester, Jessica, Marsden, Morgan, Sabberwal, Pragati, Wellington, Danielle, Dimonte, Sandra, Clare, Simon, Harcourt, Katherine, Yin, Zixi, Nobre, Luis, Antrobus, Robin, Jin, Boquan, Chen, Meixin, Makvandi-Nejad, Shokouh, Lindborg, Jane, Strittmatter, Stephen, Weekes, Michael, Stanton, Richard, Dong, Tao and Humphreys, Ian 2021. IFITM3 regulates virus-induced inflammatory cytokine production by titrating Nogo-B orchestration of TLR responses. Biorxiv

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Abstract

Interferon induced transmembrane protein 3 (IFITM3) is an important viral restriction factor in viral pathogenesis that also exhibits poorly understood immune regulatory functions. Here, using human and mouse models, we demonstrate that IFITM3 regulates MyD88-dependent TLR-mediated cytokine production following dendritic cell exposure to cytomegalovirus (CMV), and this process limits viral pathogenesis in vivo. IFITM3 also restricted pro-inflammatory (IL-6) cytokine production in response to influenza. IFITM3 bound to and promoted ubiquitination and proteasomal degradation of the reticulon 4 isoform Nogo-B. We reveal that Nogo-B mediates TLR-dependent pro-inflammatory cytokine production and promotes viral pathogenesis in vivo, and this process involved alteration of TLR dynamics. The anti-inflammatory function of IFITM3 was intrinsically linked to its ability to regulate Nogo-B. Thus, we uncover Nogo-B as an unappreciated driver of viral pathogenesis and highlight a novel immune regulatory pathway where IFITM3 fine-tunes TLR responsiveness of myeloid cells to viral stimulation.

Item Type: Article
Date Type: Published Online
Status: Submitted
Schools: Medicine
Last Modified: 01 Sep 2021 11:45
URI: http://orca.cardiff.ac.uk/id/eprint/143599

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