Long noncoding RNAs (lncRNAs) involved in the regulation of antiviral innate immune responses need to be further identified. By functionally screening the lncRNAs in macrophages, here we identified lncRNA Malat1, abundant in the nucleus but significantly down-regulated after viral infection, as a negative regulator of antiviral type I IFN (IFN-I) production. Malat1 directly bound to the transactive response DNA-binding protein (TDP43) in the nucleus and prevented activation of TDP43 by blocking the activated caspase-3-mediated TDP43 cleavage to TDP35. The cleaved TDP35 increased the nuclear IRF3 protein level by binding and degrading Rbck1 pre-mRNA to prevent IRF3 proteasomal degradation upon viral infection, thus selectively promoting antiviral IFN-I production. Deficiency of Malat1 enhanced antiviral innate responses in vivo, accompanying the increased IFN-I production and reduced viral burden. Importantly, the reduced MALAT1, augmented IRF3, and increased IFNA mRNA were found in peripheral blood mononuclear cells (PBMCs) from systemic lupus erythematosus (SLE) patients. Therefore, the down-regulation of MALAT1 in virus-infected cells or in human cells from autoimmune diseases will increase host resistance against viral infection or lead to autoinflammatory interferonopathies via the increased type I IFN production. Our results demonstrate that the nuclear Malat1 suppresses antiviral innate responses by targeting TDP43 activation via RNA-RBP interactive network, adding insight to the molecular regulation of innate responses and autoimmune pathogenesis.
The cellular and molecular components required for the formation of premetastatic niche (PMN) to promote lung metastasis need to be further investigated. Lung epithelial cells have been reported to exhibit immunomodulatory roles in lung homeostasis and also to mediate immunosuppressive PMN formation in lung metastasis. Here, by single-cell sequencing, we identified a tumor-polarized subpopulation of alveolar type 2 (AT2) epithelial cells with increased expression of glutathione peroxidase 3 (GPX3) and high production of interleukin (IL)-10 in the PMN. IL-10-producing GPX3 + AT2 cells inhibited CD4 + T cell proliferation but enhanced regulatory T cell generation. Mechanistically, tumor exosome-inducing GPX3 expression is required for GPX3 + AT2 cells to preferentially produce IL-10 by stabilizing hypoxia-inducible factor 1 (HIF-1α) and promoting HIF-1α-induced IL-10 production. Accordingly, conditional knockout of GPX3 in AT2 cells suppressed lung metastasis in spontaneous metastatic models. Together, our findings reveal a role of tumor-polarized GPX3 + AT2 cells in promoting lung PMN formation, adding insights into immune evasion in lung metastasis and providing potential targets for the intervention of tumor metastasis.
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