Abstract
Nuclear factor 90 (NF90) is a novel virus sensor that serves to initiate antiviral innate immunity by triggering stress granule (SG) formation. However, the regulation of the NF90-SG pathway remains largely unclear. We found that Tim-3, an immune checkpoint inhibitor, promotes the ubiquitination and degradation of NF90 and inhibits NF90-SG-mediated antiviral immunity. Vesicular stomatitis virus (VSV) infection induces the up-regulation and activation of Tim-3 in macrophages, which in turn recruit the E3 ubiquitin ligase TRIM47 to the zinc finger domain of NF90 and initiate a proteasome-dependent degradation via K48-linked ubiquitination at Lys297. Targeted inactivation of Tim-3 enhances the NF90 downstream SG formation by selectively increasing the phosphorylation of protein kinase R and eukaryotic translation initiation factor 2α, the expression of SG markers G3BP1 and TIA-1, and protecting mice from VSV challenge. These findings provide insights into the crosstalk between Tim-3 and other receptors in antiviral innate immunity and its related clinical significance.
Highlights
Innate immunity is the first line of host defense against viral infection
To test whether Tim-3 is involved in the innate immunity against viruses, we challenged macrophages with Vesicular stomatitis virus (VSV), an RNA virus widely used for investigating anti-viral immunity in both mouse and human models (Chen et al, 2013)
nuclear factor 90 (NF90) was found to play an important role in host innate immunity against various virus infections
Summary
Innate immunity is the first line of host defense against viral infection. Pattern recognition receptors (PRRs), including Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs), are main sensors in defending virus infection (Chen et al, 2013). PRR-mediated downstream signaling pathways initiating an anti-viral innate immune response is the classic anti-virus infection model (Barbalat et al, 2011; McFadden et al, 2017). NF90 is an evolutionarily conserved member of the double-stranded RNA (dsRNA)-binding protein family and is abundantly expressed in various mammalian cells (Patino et al, 2015; Masuda et al, 2013). As an important antiviral pathway, NF90 recognizes virus dsRNA and triggers the formation of stress granules (SGs), which are composed of cytoplasmic particles including ribonucleoproteins, RNA-binding proteins, and translation initiation factors (Shi et al, 2007). An understanding of the precise regulation mechanisms of NF90-SG signaling for efficient viral clearance without harmful immunopathology is needed
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