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). Recently, studies have found that nuclear factor 90 (NF90), which is encoded by interleukin enhancer-binding factor-3, is a critical sensor for invading viruses (Li et al., 2016; Shabman et al., 2011; Wang et al., 2009; Wen et al., 2014; Pfeifer et al., 2008). NF90 is an evolutionarily conserved member of the double-stranded RNA (dsRNA)-binding protein family and is abundantly expressed in various mammalian cells (Patiño 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). Unfortunately, a growing number of virus families modulate SG formation and function to maximize replication efficiency (White and Lloyd, 2012). Therefore, an understanding of the precise regulation mechanisms of NF90-SG signaling for efficient viral clearance without harmful immunopathology is needed.

Upon sensing virus, NF90 induces the phosphorylation of dsRNA-activated protein kinase R (PKR) (Li et al., 2016; Wen et al., 2014). Then SGs form following PKR-mediated phosphorylation and activation of the eukaryotic translation initiation factor 2α (eIF2α), which induces the expression of G3BP1 (Tsai et al., 2017) (Ras-GAP SH3-binding protein-1) and TIA-1 (T-cell intracellular antigen-1), two key markers in SGs. The activated eIF2α co-operates with other components of SGs to block virus mRNA translation. Despite acting as an important virus sensor and trigger of SG formation, how NF90 is regulated remains largely unknown.

Tim-3, encoded by the hepatitis A virus cellular receptor two gene (Havcr2), is an immune checkpoint inhibitor that was first identified in activated T cells. Later, Tim-3 was also found to be expressed in innate immune cells, such as dendritic cells and macrophages (Han et al., 2013). Establishment of Tim-3 as an exhaustion marker in immune cells of both tumors and infectious diseases makes Tim-3 an attractive target for immunotherapy similar to PD-1 (Huang et al., 2015), CTLA-4 (Stamper et al., 2001), and Siglec-G (Rangachari et al., 2012). Recently, a report showed that increased Tim-3 expression on immune cells in patients with coronavirus disease (COVID-19) is associated with an exhaustion phenotype (Diao et al., 2020). However, Tim-3 does not have an inhibitory motif within its tail (van de Weyer et al., 2006), and the mechanism by which Tim-3 mediates inhibitory signaling remains largely unclear. Huang et al., 2015 showed that CEACAM1 is a heterophilic ligand of Tim-3 and is required for Tim-3 to mediate T cell inhibition and that Bat-3 acts as a safety catch, which blocks Tim-3-mediated inhibitory signals in T cells (Rangachari et al., 2012). Potentiating anti-infection immunity by inducing innate immune responses is a promising area of infection therapy. However, little is known about Tim-3 signaling in innate immune cells.

Ubiquitination is one of the most versatile posttranslational modifications and is indispensable for antiviral infection (Heaton et al., 2016). Increasing evidences suggest that ubiquitination plays important roles in various cellular processes, including cell proliferation and antiviral innate signaling. Posttranslational modification of many signaling molecules, including TRAF3/6 (Chen et al., 2015), RIG-I (Chen et al., 2013), MAVS (Liu et al., 2017), TBK1 (Song et al., 2016a), IRF3/7 (Yu and Hayward, 2010; Wang et al., 2015), and NLRP3 (Song et al., 2016b), involved in TLR, RLR, and NLR pathways by different types of ubiquitination plays key roles in the regulation of antiviral innate immunity. However, whether NF90, a molecule containing a ubiquitin-binding domain (domain associated with zinc fingers, DZF), undergoes ubiquitination remains unclear.

Here we found that Tim-3 was involved in innate immunity against vesicular stomatitis virus (VSV) by promoting the proteasomal degradation of NF90 via the tripartite motif-containing protein 47 (TRIM47)-mediated conjugation of K48-linked ubiquitin. To the best of our knowledge, it is the first time demonstrating ubiquitination as a new posttranslational modification mechanism of NF90. Our findings shed a new light on the Tim-3-mediated immune tolerance during infection.

Viruses have developed many different strategies of immune evasion, for example, by downregulating or degrading virus sensors. The mechanisms by which these receptors are regulated are widely investigated in hopes of developing effective treatments. NF90 was found to play an important role in host innate immunity against various virus infections. However, the regulation of NF90 under physiopathological conditions remains largely unclear. Here we have identified a novel negative regulation mechanism of NF90, which could be employed by VSV to evade the immune attack. The VSV-activated Tim-3 in turn promotes the ubiquitination and degradation of NF90 and subsequently inhibits the formation and antiviral activity of downstream SGs. To the best of our knowledge, this is the first report showing that NF90 undergoes ubiquitination and also the critical domain (DZF) and critical site (Lys297) of NF90 for Tim-3- and E3 ligase TRIM47-mediated ubiquitination and degradation.

NF90, like the classical PRRs, is considered a novel virus sensor, exerting an important role in host innate immunity against various viral infections, especially negative-sense single-stranded RNA viruses (Li et al., 2016; Wang et al., 2009; Wen et al., 2014). One report showed that NF90 is required for an efficient response against VSV infection (Pfeifer et al., 2008), but the underlying mechanism has not been clarified. Other reports have shown that NF90 interacted with the VP35 protein of Ebola virus (EBOV) and inhibited EBOV infection through impairing the function of the EBOV transcription/replication complex (Shabman et al., 2011). Knockdown of NF90 in indicated cells dramatically promotes EBOV and influenza virus replication, while overexpression of NF90 inhibits or impacts replication of these viruses (Li et al., 2016; Shabman et al., 2011; Wang et al., 2009). When the signaling cascades were investigated, SGs, not the interferon pathway, served as the downstream signaling cascade of the NF90 antiviral pathway (Shabman et al., 2011; Pfeifer et al., 2008). NF90 promotes (Meunier et al., 2014) the assemblage of SG and synergizes with other proteins to exert antiviral immunity (Wen et al., 2014). These reports support our findings that NF90 inhibits VSV replication via SGs and further demonstrate the critical role of the NF90-SG signaling pathway during an antiviral immune response.

Tim-3 is an immune checkpoint inhibitor that was initially found to be expressed on activated Th1 cells by binding with its ligand Gal-9 (Chou et al., 2009; Dardalhon et al., 2010). Tim-3 induces apoptosis and T cell tolerance (Nakayama et al., 2009; Sarraj et al., 2014). Most investigations focus on the roles of Tim-3 in maintaining T cell exhaustion in immune disorders, tumors, or infectious diseases, which means that this checkpoint inhibitor could be abused. Recently, our works and other published data have focused on the roles of Tim-3 in maintaining the homeostasis of innate immune cells and have demonstrated that the dysregulated Tim-3 on innate immune cells also contributes to the immune evasion of many tumors or pathogens (Diao et al., 2020; Jiang et al., 2016). Innate immune cells have now attracted much attention for developing new therapeutic strategies against infectious or tumor diseases, in which innate immune cell-expressed immune checkpoint inhibitors are potential targets (Han et al., 2013). Here we have found that Tim-3 suppresses the macrophage-mediated antiviral immune response, suggesting that it is a potent therapeutic target for re-boosting innate immunity against viruses. However, as Tim-3 does not possess an obviously classical Immunoreceptor Tyrosine-based Inhibition Motif (ITIM)motif compared with other immune-checkpoint receptors, such as PD-1, CTLA-4 (Stålhammar et al., 2019), and Siglec-G (Chen et al., 2013), the mechanism by which Tim-3 mediates inhibitory signals remains unclear. Huang et al., 2015 showed that Tim-3 induces T cell exhaustion via Human leucocyte antigen B associated transcript (BAT) and using CEACAM1 as a coreceptor, and our findings have shown that Tim-3 promotes tumor-prone macrophage polarization by binding to and suppressing the phosphorylation and nuclear translocation of STAT1 (Jiang et al., 2016) Further, Tim-3 inhibits TLR4-mediated macrophage activation during sepsis by suppressing NF-kB activation (Yang et al., 2013). How Tim-3 works during anti-viral innate immunity remains unclear. The intracellular tail of Tim-3 contains a highly conserved tyrosine-containing src homology 2 (SH2)-binding motif, and tyrosine residues within this motif can be phosphorylated, which is critical for Tim-3 signaling in T cells (Chen et al., 2013). In this study, we have identified an increased tyrosine phosphorylation of Tim-3 in macrophages following VSV infection. We have also demonstrated that deletion of Tim-3 tail or mutation of the conserved tyrosines, including Tyr265, Tyr272, Tyr280, and Try281, within Tim-3 tail significantly attenuated the interaction between Tim-3 and NF90. These data demonstrated a new mechanism by which Tim-3 transduces inhibitory signal in anti-viral innate immune responses.

Ubiquitination is one of the most versatile posttranslational modifications for substrates and is indispensable for antiviral infection (Callis, 2014). However, whether NF90 undergoes ubiquitination is totally unknown. Structurally, NF90 possesses a DZF in the N-terminal region, which is a symbol of ubiquitination for substrates (Ji et al., 2018). Here we have verified our hypothesis and demonstrated that NF90 can be ubiquitinated, a process that is enhanced by Tim-3 in macrophages following VSV infection. As speculated, Tim-3 mainly promotes the ubiquitination of the DZF domain of NF90. To the best of our knowledge, this is the first report demonstrating that NF90 undergoes ubiquitination. Further, we have also found that Lys297, a highly conserved residue among different isoforms of NF90, plays a critical role in the K-48-linked ubiquitination of NF90.

When the candidates accounting for NF90 ubiquitination were examined, we focused on TRIM47 as it got the highest scores and the highest number of matched peptides among NF90-interacting proteins, and structurally, TRIM47 contains a RING finger domain in the N-terminus, which may contribute to ubiquitin modification (Ji et al., 2018). In addition, TRIM family proteins play important roles in many biological processes, such as cell cycle regulation and viral response (Wang et al., 2015). As discussed above, the conserved tyrosines within the Tim-3 tail could form an SH2 (SRC homology 2)-binding domain (Rangachari et al., 2012; van de Weyer et al., 2006; Jiang et al., 2016; Lee et al., 2011). We posit that Tim-3 may recruit TRIM47 using its SH2-binding domain as the tyrosines are phosphorylated following VSV infection. A recent report showing that Siglec-G triggers downstream signaling by recruiting SHP-2 (Chen et al., 2013) supports this hypothesis. Here we have demonstrated that TRIM47 dose-dependently promotes the proteasome-dependent degradation of NF90 (Figure 4B). However, to the best of our knowledge, no well-defined ligase-dead TRIM47 construct(s) has been reported so far. The mechanisms by which TRIM47 promotes NF90 degradation remain to be determined in the future. Interestingly, our data showed that Tim-3 enhances the expression and ubiquitination of TRIM47. This is also the first report showing the ubiquitination modification of TRIM47. However, the mechanisms of Tim-3-enhanced TRIM47 ubiquitination and whether the enhanced ubiquitination of TRIM47 by Tim-3 accounts for the increased TRIM47 expression remain to be determined.

In summary, we have verified that Tim-3 is specifically upregulated following VSV infection and inhibits NF90 signaling pathway in macrophages. Intracellularly, Tim-3 promotes TRIM47-mediated ubiquitination and degradation of NF90. In VSV-infected models, Tim-3 signaling inhibits the formation and the activity of the NF90 downstream SGs. To the best of our knowledge, this is the first report demonstrating the ubiquitination modification of NF90. These findings provide a novel mechanism of Tim-3-mediated infection tolerance, which has implications in antiviral applications.

All data generated or analysed during this study are included in the manuscript and supporting files.

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Author details

1. Shuaijie Dou

   1. Beijing Institute of Basic Medical Sciences, Beijing, China
   2. Anhui Medical University, Hefei, China

   Contribution

   Formal analysis, Investigation, Methodology

   Contributed equally with

   Guoxian Li and Ge Li

   Competing interests

   No competing interests declared

2. Guoxian Li

   1. Beijing Institute of Basic Medical Sciences, Beijing, China
   2. Institute of Immunology, Medical School of Henan University, Kaifeng, China

   Contribution

   Investigation, Methodology

   Contributed equally with

   Shuaijie Dou and Ge Li

   Competing interests

   No competing interests declared

3. Ge Li

   Beijing Institute of Basic Medical Sciences, Beijing, China

   Contribution

   Data curation, Formal analysis, Project administration

   Contributed equally with

   Shuaijie Dou and Guoxian Li

   Competing interests

   No competing interests declared

4. Chunmei Hou

   Beijing Institute of Basic Medical Sciences, Beijing, China

   Contribution

   Methodology

   Competing interests

   No competing interests declared

5. Yang Zheng

   Department of Oncology, First Hospital of Jilin University, Changchun, China

   Contribution

   Formal analysis, Methodology

   Competing interests

   No competing interests declared

6. Lili Tang

   Beijing Institute of Basic Medical Sciences, Beijing, China

   Contribution

   Investigation, Project administration

   Competing interests

   No competing interests declared

7. Yang Gao

   Beijing Institute of Basic Medical Sciences, Beijing, China

   Contribution

   Investigation, Methodology

   Competing interests

   No competing interests declared

8. Rongliang Mo

   Beijing Institute of Basic Medical Sciences, Beijing, China

   Contribution

   Data curation, Investigation

   Competing interests

   No competing interests declared

9. Yuxiang Li

   Beijing Institute of Basic Medical Sciences, Beijing, China

   Contribution

   Data curation, Investigation

   Competing interests

   No competing interests declared

10. Renxi Wang

    1. Beijing Institute of Basic Medical Sciences, Beijing, China
    2. Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, China

    Contribution

    Conceptualization, Project administration

    For correspondence

    wang_renxi@hotmail.com

    Competing interests

    No competing interests declared

11. Beifen Shen

    Beijing Institute of Basic Medical Sciences, Beijing, China

    Contribution

    Conceptualization, Funding acquisition

    Competing interests

    No competing interests declared

12. Jun Zhang

    Institute of Immunology, Medical School of Henan University, Kaifeng, China

    Contribution

    Data curation, Investigation, Project administration

    For correspondence

    zhangjun@henu.edu.cn

    Competing interests

    No competing interests declared

13. Gencheng Han

    Beijing Institute of Basic Medical Sciences, Beijing, China

    Contribution

    Formal analysis, Funding acquisition, Validation, Project administration, Writing - review and editing

    For correspondence

    genchenghan@163.com

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0003-1408-878X

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