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

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.

Interferon‐induced transmembrane protein 3 (IFITM3) limits lethality of SARS‐CoV‐2 in mice

“…Elevated levels of the inflammatory cytokines IL‐6, TNFα, and IL‐1β were also detected in KO versus WT lungs at Day 3 postinfection (Fig 1E ), likely due to higher viral burden in the lung. Alternatively, these results are consistent with feedback inhibition of type I interferon induction and inflammation by IFITM3, as has been previously suggested (Jiang et al , 2017 ; Stacey et al , 2017 ; Clement et al , 2022 ). Viral titers were decreased in both groups between Days 2 and 5 (Fig 1D ).…”

Systems biology analysis reveals distinct molecular signatures associated with immune responsiveness to the BNT162b COVID-19 vaccine

“… 45 Similarly, PLEK is involved in maturation of monocytes and their differentiation to dendritic cells following vaccination, 46 while CIITA is a known master regulator of MHC-II expression. 47 , 48 Along these lines, IFITM3 and ISG20 both play indispensable non-binary roles in regulating inflammatory cytokine production 49 and degradation of non-self RNA, 50 , 51 while CXCL10 is a well described chemokine secreted by monocytes and migratory dendritic cells following a viral challenge. 52 , 53 , 54 All of the above strongly implies clusters 2 and 4 as being activated monocytes with a DC-like phenotype.…”

Genome-wide CRISPR activation screen identifies JADE3 as an antiviral activator of NF-kB–dependent IFITM3 expression

“…This is especially important given that NF-kB has been shown to have both antiviral and proviral roles, including in the context of IAV infection ( 68 , 69 , 70 ). Alternatively, prior evidence shows IFITM3 functions in a feedback loop to inhibit both IFN and NF-kB signaling potentially explaining the activation of NF-kB in JADE3 KO cells ( 71 , 72 ). JADE3’s activation of NF-kB signaling was dependent on its PHD domains, suggesting its role in chromatin regulation is required ( Fig.…”