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

Clement, Mathew ORCID: https://orcid.org/0000-0002-9280-5281, 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 ORCID: https://orcid.org/0000-0002-6799-1182, Dong, Tao and Humphreys, Ian ORCID: https://orcid.org/0000-0002-9512-5337 2021. IFITM3 regulates virus-induced inflammatory cytokine production by titrating Nogo-B orchestration of TLR responses. [Online]. bioRxiv. Available at: https://doi.org/10.1101/2021.07.23.453513

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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:	Website Content
Date Type:	Published Online
Status:	Submitted
Schools:	Medicine
Publisher:	bioRxiv
Last Modified:	27 Jul 2023 01:06
URI:	https://orca.cardiff.ac.uk/id/eprint/143599

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