IFITM3 restricts virus-induced inflammatory cytokine production by limiting Nogo-B mediated TLR responses

Clement, M. ORCID: https://orcid.org/0000-0002-9280-5281, Forbester, J. L., Marsden, M., Sabberwal, P., Sommerville, M. S., Wellington, D., Dimonte, S., Clare, S., Harcourt, K., Yin, Z., Nobre, L., Antrobus, R., Jin, B., Chen, M., Makvandi-Nejad, S., Lindborg, J. A., Strittmatter, S. M., Weekes, M. P., Stanton, R. J. ORCID: https://orcid.org/0000-0002-6799-1182, Dong, T. and Humphreys, I. R. ORCID: https://orcid.org/0000-0002-9512-5337 2022. IFITM3 restricts virus-induced inflammatory cytokine production by limiting Nogo-B mediated TLR responses. Nature Communications 13 (1) , 5294. 10.1038/s41467-022-32587-4

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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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	Nature Research
ISSN:	2041-1723
Funders:	Wellcome Trust, MRC
Date of First Compliant Deposit:	12 September 2022
Date of Acceptance:	8 August 2022
Last Modified:	11 Oct 2023 20:32
URI:	https://orca.cardiff.ac.uk/id/eprint/152472

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