IFITM3 restricts virus-induced inflammatory cytokine production by limiting Nogo-B mediated TLR responses.
Mathew ClementJ L ForbesterM MarsdenP SabberwalM S SommervilleDannielle WellingtonS DimonteS ClareK HarcourtZixi YinL NobreR AntrobusB JinM ChenS Makvandi-NejadJ A LindborgStephen M StrittmatterMichael P WeekesRichard James StantonT DongIan R HumphreysPublished in: Nature communications (2022)
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.
Keyphrases
- sars cov
- toll like receptor
- dendritic cells
- immune response
- inflammatory response
- nuclear factor
- high glucose
- endothelial cells
- oxidative stress
- respiratory syndrome coronavirus
- induced apoptosis
- gene expression
- genome wide
- regulatory t cells
- epstein barr virus
- small molecule
- dna methylation
- cell cycle arrest
- signaling pathway
- binding protein
- cell death
- air pollution
- endoplasmic reticulum stress
- coronavirus disease