tetano
Editor, Senior Moderator
Nat Commun
. 2022 Sep 8;13(1):5294.
doi: 10.1038/s41467-022-32587-4.
IFITM3 restricts virus-induced inflammatory cytokine production by limiting Nogo-B mediated TLR responses
M Clement[SUP] #[/SUP][SUP] 1 [/SUP], J L Forbester[SUP] #[/SUP][SUP] 1 2 [/SUP], M Marsden[SUP] 1 [/SUP], P Sabberwal[SUP] 1 [/SUP], M S Sommerville[SUP] 1 [/SUP], D Wellington[SUP] 2 3 [/SUP], S Dimonte[SUP] 1 [/SUP], S Clare[SUP] 4 [/SUP], K Harcourt[SUP] 4 [/SUP], Z Yin[SUP] 2 3 [/SUP], L Nobre[SUP] 5 [/SUP], R Antrobus[SUP] 5 [/SUP], B Jin[SUP] 6 [/SUP], M Chen[SUP] 7 [/SUP], S Makvandi-Nejad[SUP] 2 [/SUP], J A Lindborg[SUP] 8 [/SUP], S M Strittmatter[SUP] 8 [/SUP], M P Weekes[SUP] 5 [/SUP], R J Stanton[SUP] 1 [/SUP], T Dong[SUP] 2 3 [/SUP], I R Humphreys[SUP] 9 [/SUP]
Affiliations
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.
. 2022 Sep 8;13(1):5294.
doi: 10.1038/s41467-022-32587-4.
IFITM3 restricts virus-induced inflammatory cytokine production by limiting Nogo-B mediated TLR responses
M Clement[SUP] #[/SUP][SUP] 1 [/SUP], J L Forbester[SUP] #[/SUP][SUP] 1 2 [/SUP], M Marsden[SUP] 1 [/SUP], P Sabberwal[SUP] 1 [/SUP], M S Sommerville[SUP] 1 [/SUP], D Wellington[SUP] 2 3 [/SUP], S Dimonte[SUP] 1 [/SUP], S Clare[SUP] 4 [/SUP], K Harcourt[SUP] 4 [/SUP], Z Yin[SUP] 2 3 [/SUP], L Nobre[SUP] 5 [/SUP], R Antrobus[SUP] 5 [/SUP], B Jin[SUP] 6 [/SUP], M Chen[SUP] 7 [/SUP], S Makvandi-Nejad[SUP] 2 [/SUP], J A Lindborg[SUP] 8 [/SUP], S M Strittmatter[SUP] 8 [/SUP], M P Weekes[SUP] 5 [/SUP], R J Stanton[SUP] 1 [/SUP], T Dong[SUP] 2 3 [/SUP], I R Humphreys[SUP] 9 [/SUP]
Affiliations
- PMID: 36075894
- DOI: 10.1038/s41467-022-32587-4
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.