发病机制
TLR2型
细胞因子
细胞生物学
病毒病机
跨膜蛋白
生物
炎症
病毒
免疫学
信号转导
TLR4型
病毒复制
受体
生物化学
作者
Mathew Clement,Jessica L. Forbester,Morgan Marsden,Pragati Sabberwal,M. S. Sommerville,Dannielle Wellington,Sandra Dimonte,Simon Clare,Katherine Harcourt,Zixi Yin,Luís Nobre,Robin Antrobus,Boquan Jin,M. Chen,Shokouh Makvandi‐Nejad,Jane A. Lindborg,Stephen M. Strittmatter,Michael P. Weekes,Richard J. Stanton,Tao Dong,Ian R. Humphreys
标识
DOI:10.1038/s41467-022-32587-4
摘要
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.
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