Fish CDK2 recruits Dtx4 to degrade TBK1 through ubiquitination in the antiviral response

Interferon (IFN) production is central to the host’s innate immune response to viral infections. IFN acts as a ligand, binding to receptors on neighboring cell membranes through the autocrine and paracrine pathways, which initiates the Janus kinase/signal transducer and activator of the transcription (JAK/STAT) signaling pathway (Kisseleva et al., 2002). This, in turn, leads to the transcription of a large number of antiviral genes, ultimately resulting in the clearance of intracellular viral components (Sadler and Williams, 2008). IFN induction depends on cellular pattern recognition receptors (PRRs) and sensing of conserved pathogen-associated molecular patterns (PAMPs), with the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) signaling pathway being critical in this system (Kumar et al., 2011). Viral nucleic acids are recognized by the RLRs, which then initiate a series of signaling events that lead to downstream IFN expression. TANK-binding kinase 1 (TBK1) efficiently phosphorylates IFN regulatory factor 3/7 (IRF3/7), facilitating its nuclear entry (Fitzgerald et al., 2003).

Effective control of IFN production is crucial during viral infection in maintaining immune responses and homeostasis, whereby excessive IFN can cause inflammatory storms that harm the organism. Hence, TBK1 plays a significant role in the IFN signaling pathway and is negatively regulated by various factors to balance IFN expression in the host (Zhao, 2013). Mammalian TBK1 is degraded by NLRP4, which recruits the E3 ubiquitin ligase DTX4 for K48-linked polyubiquitination at Lys670 (Cui et al., 2012). Additionally, DYRK2 is crucial in the degradation of TBK1 by NLRP4 through the phosphorylation of Ser527, as mentioned in previous studies (Cui et al., 2012; An et al., 2015). The function of TBK1 is conserved in fish and subject to modulation by multiple molecules to prevent excessive IFN expression. Indeed, TMEM33 in zebrafish serves as a TBK1 substrate, reducing IRF3 phosphorylation and hindering TBK1 kinase activity to diminish IFN expression (Lu et al., 2021). Generally, the ability of TBK1 to induce IFN is conserved and tightly regulated within the host.

CDKs are a family of Ser/Thr kinases that act as cell cycle regulators. Cell cycle progression from the G1 phase to the S phase and from G2 to mitosis is controlled by various cyclin–CDK complexes. For example, CDK2 and cyclin E regulate the G1–S transition (Fagundes and Teixeira, 2021). Further studies have unveiled other functions of the CDK family in biological processes beyond cell cycle regulation. The transcription of multiple proinflammatory genes is upregulated in a CDK-dependent fashion throughout the G1 phase (Schmitz and Kracht, 2016). In the context of antitumor immunity in fibrosarcoma and lung carcinoma, inhibiting CDK2 leads to the RB protein being phosphorylated, which results in increased production of type I IFN (Chen et al., 2022). Another study demonstrated that inhibiting CDKs or the knockdown of CDKs activities caused a significant blockade in IFN release from culture supernatants (Cingöz and Goff, 2018). While there are several reported functions of CDKs in innate immunity, understanding the roles of CDKs in this area remains unclear.

The immune systems of higher vertebrates (e.g. humans) and lower vertebrates (e.g. fish) generally exhibit some consistency, although there are notable differences. For instance, IFN phosphorylates fish IRF3, which is only phosphorylated by viruses in mammals. Additionally, fish MVP functions as an IFN-negative regulator, while human MVP mediates IFN-positive expression (Sun et al., 2010; Panne et al., 2007; Li et al., 2019; Liu et al., 2012). There are 13 CDK genes in the human genome and 21 CDK orthologs in zebrafish, indicating that CDK functions are conserved and differ between fish and humans. Our report reveals that fish CDK2 acts as an IFN negative regulator that recruits Dtx4 to facilitate the ubiquitination of TBK1, thereby restricting IFN expression. These findings offer valuable insights into the various roles of CDK2.

Although IFN responses exhibit powerful functions in defending against viral infection, excessive activation of IFN production may cause autoimmune disease. Therefore, the host needs to develop a set of regulatory mechanisms to balance immune responses. In this study, we illustrated a novel role for fish CDK2 in the negative regulation of IFN expression, which degraded TBK1 for K48-linked ubiquitination by recruiting E3 ubiquitin ligase Dtx4.

TBK1 is a central kinase in MAVS, STING, and TIR-domain-containing adapter-inducing IFN-β (TRIF) signaling complexes, which promote the phosphorylation of IRF3 and the production of IFN. Thus, the activation of TBK1 must be tightly regulated to avoid excessive autoimmune responses. TBK1 activity can be regulated in various ways, including phosphorylation, ubiquitination, SUMOylation, and preventing the formation of functional TBK1-containing complexes. For instance, receptor tyrosine kinase HER2 recruits AKT1 to directly phosphorylate TBK1, which disrupts the TBK1–STING association and K63-linked ubiquitination of TBK1, thus suppressing antiviral responses (Wu et al., 2019). Siglec1 associates with DAP12 and SHP2 to recruit the E3 ubiquitin ligase TRIM27, which induces K48-linked-ubiquitination-mediated TBK1 degradation, resulting in the inhibition of IFN production (Zheng et al., 2015). Similar to mammals, TBK1 also dramatically activates the IFN signaling pathway in fish. Therefore, its activation must be precisely modulated. For example, cytokine receptor-like factor 3 (Crlf3) promotes the degradation of TBK1 via K48-linked ubiquitination, resulting in inhibition of IFN production (Yan et al., 2023). While TBK1 regulation has received attention, multiple molecules and underlying molecular mechanisms have not been fully characterized as potential TBK1 targets.

Ubiquitination is one of the most versatile post-translational modifications (PTMs) of proteins and plays numerous vital roles in regulating antiviral responses. Ubiquitin comprises seven lysine residues (K6, K11, K27, K29, K33, K48, and K63); thus, seven different polyubiquitin chains can be produced (Song and Luo, 2019). K48-linked polyubiquitination is used to signal for proteasomal degradation of substrate proteins. In contrast, K63-linked polyubiquitination is a non-proteolytic mode of modification that plays several vital roles in stabilizing and activating target proteins (Kulathu and Komander, 2012). Multiple studies have shown that different polyubiquitin chains can regulate the expression and activation of TBK1 (Zhao, 2013). For instance, Nrdp1, MIB1/2, RNF128, and NLRC4 mediate the K63‐linked polyubiquitination of TBK1 and facilitate its activation (Wang et al., 2009; Ye et al., 2014; Song et al., 2016; Zhang et al., 2023). TRIP, SOCS3, and TRAF3IP3 have been proven to negatively regulate the IFN signaling pathway by targeting TBK1 for K48-linked polyubiquitination and degradation (Zhang et al., 2012; Liu et al., 2015; Deng et al., 2020). Ubiquitination modification is a tightly regulated and reversible process that maintains cellular homeostasis. For example, the deubiquitinating enzymes CYLD, RNF114B, USP2b, and UBE2S remove the K63-linked polyubiquitination of TBK1 to block its activation (Friedman et al., 2008; Zhang et al., 2019; Zhang et al., 2014; Huang et al., 2020). Additionally, the USP1–UAF1 deubiquitinate complex has been found to cleave the K48‐linked polyubiquitination of TBK1 to reverse its degradation process (Yu et al., 2017). These findings are specific to the ubiquitination of mammalian TBK1. Although fish TBK1 is highly conserved compared to mammalian TBK1, its ubiquitination modifications are worth exploring. Our study identified a previously unrecognized role for CDK2 in promoting the K48‐linked polyubiquitination and proteasomal degradation of fish TBK1.

A series of ubiquitin-related enzymes are responsible for ubiquitination, including ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), and ubiquitin ligases (E3s). Among them, the E3s are the critical components that determine the substrate specificity (Pickart, 2001). E3s are generally divided into two large classes, including the homology to the E6-associated protein carboxyl terminus (HECT) domain-containing E3 ligases and the really interesting new gene (RING) domain-containing E3 ligases (Metzger et al., 2012). Multiple studies have demonstrated that E3 ligases, including TRIP, Socs3, Dtx4, and TRIM27, specifically target TBK1 for K48-linked polyubiquitination and degradation (Zheng et al., 2015; Zhang et al., 2012; Liu et al., 2015; Cui et al., 2012). However, CDK2 is not an E3 ubiquitin ligase. Thus, we reasoned that CDK2 might be a mediator in the recruitment of an E3 ubiquitin ligase for K48-linked polyubiquitination. To validate this hypothesis, we investigated and screened hTBK1-associated E3 ubiquitin ligases, demonstrating that Dtx4 interacted with CDK2 and enhanced the K48-linked polyubiquitination of TBK1. Meanwhile, our results showed that the RING domain in Dtx4 was necessary for modifying TBK1 through ubiquitination.

Recent studies have demonstrated that CDK activity is crucial for virus-induced innate immune responses (Zheng and Tang, 2022). Reports indicate that CDKs are involved in the Toll-like receptor (TLR) signaling pathway, the nuclear factor-κB (NF-κB) signaling pathway, and the JAK-STAT signaling pathway. For instance, CDK8 and/or CDK19 enhanced the transcription of inflammatory genes, such as IL-8 and IL-10, in cells following TLR9 stimulation (Yamamoto et al., 2017). CDKs and NF-κB establish a remarkable paradigm where CDKs can act directly on substrate proteins rather than depending solely on transcriptional control (Perkins et al., 1997). It has been reported that CDK1 serves as a positive regulator of the IFN-I signaling pathway, facilitating STAT1 phosphorylation, which subsequently boosts the expression of ISGs (Wu et al., 2016). Furthermore, inhibiting CDK activity has been shown to obstruct STAT phosphorylation, proinflammatory gene activation, and ISG mRNA induction in response to SeV infection (Cingöz and Goff, 2018). It is important to note that no evidence suggests the involvement of CDKs in RLR signaling pathways. This study has shown that fish CDK2 functions as a negative regulator of the key kinase TBK1, which is involved in the RLR signaling pathway. Variations in CDK2 activity during different phases of the cell cycle may lead to changes in the expression and function of TBK1. Our findings suggest that heightened CDK2 activity may suppress TBK1 expression, thereby hindering the cell’s capacity to produce IFN. Conversely, during the late phase of the cell cycle or in an inhibited state, TBK1 expression may rise, enhancing IFN synthesis and release. In summary, CDK2 is involved in intracellular signaling by modulating TBK1 levels and IFN production, affecting the cellular immune response and cycle regulation—two processes that are notably distinct at various stages of the cell cycle. A better understanding of the relationship between CDK2 and RLR signaling pathways will enhance our grasp of the regulatory mechanisms of CDKs in antiviral innate immunity. In addition, we now briefly propose a model wherein CDK2 activity during the S phase may suppress TBK1-mediated IFN production to allow viral replication, while CDK2 inhibition (e.g. in G1) may enhance IFN responses. This hypothesis will be the subject of our future work, including cell cycle synchronization experiments and time-course analyses of CDK2 activity and IFN output during infection.

CDK2 is a multifunctional kinase involved in many critical cellular processes, including cell cycle progression, differentiation, cancer, immunity, etc. (Tadesse et al., 2020). To date, there has been limited research conducted on fish CDK2 in the regulation of cell cycle progression. The details are as follows: It has been reported that the kinase activity of goldfish CDK2 significantly increases during oocyte maturation (Hirai et al., 1992). Furthermore, UHRF1 phosphorylation by cyclin A2/CDK2 is crucial for zebrafish embryogenesis (Chu et al., 2012). Additionally, a novel CDK2 homolog has been identified in Japanese lamprey, which plays a crucial role in apoptosis (Xu et al., 2019). Red grouper nervous necrosis virus (RGNNV) infection activates the p53 pathway, leading to the upregulation of p21 and downregulation of cyclin E and CDK2, which forces infected cells to remain in the G1/S replicative phase (Mai et al., 2018). In addition, we selected representative species from each of the six major vertebrate groups and compared their CDK2 protein sequences, discovering that they are over 90% similar to one another. This suggests that the function of CDK2 may be conserved to some extent across vertebrates. Furthermore, CDK2 inhibition has been shown to enhance anti-tumor immunity by increasing the IFN response to endogenous retroviruses (Chen et al., 2022). Here, we reveal the role of CDK2 in modulating the RLR signaling pathway during innate immunity. Upon infection with SVCV, CDK2 expression was induced. However, the precise upstream signaling pathways that regulate CDK2 during viral infection remain to be fully elucidated. It is hypothesized that viral RNA sensors may activate transcription factors that bind to the cdk2 promoter; however, further investigation is required to confirm this. CDK2 deficiency or knockdown enhanced the antiviral response both in vitro and in vivo, while CDK2 overexpression promoted viral replication. Thus, our study identifies CDK2 as a negative regulator of antiviral immune responses in addition to its well-studied function in cell cycle regulation. Meanwhile, the E3 ubiquitin ligase Dtx4 is also required to regulate antiviral immune responses. Furthermore, evidence is presented demonstrating that CDK2 enhances the interaction between Dtx4 and TBK1, thus suggesting that CDK2 functions as a scaffold protein to facilitate the formation of a ternary complex. However, further study is required to ascertain the precise structural basis of this interaction, including whether CDK2’s kinase activity is required.

In conclusion, our results identified a novel function of CDK2 in the negative regulation of TBK1-mediated IFN production. CDK2 interacted with TBK1 and recruited the E3 ubiquitin ligase Dtx4 to facilitate the K48‐linked polyubiquitination at Lys567 residues in TBK1, eventually leading to the proteasomal degradation of TBK1. Our findings have revealed a previously unrecognized role for CDK2 in regulating immune homeostasis, providing molecular insight into the mechanisms through which CDK2–DTX4 targets TBK1 for ubiquitination and degradation.

RNA sequence data were deposited in NGDC (National Genomics Data Center) (GSA accession number: CRA008409). All data generated or analyzed during this study are included in the manuscript and supporting files; source data files have been provided for all figures.

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Author details

1. Long-Feng Lu

   1. Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
   2. University of Chinese Academy of Sciences, Beijing, China

   Contribution

   Conceptualization, Data curation, Funding acquisition, Writing – original draft

   Competing interests

   No competing interests declared

2. Can Zhang

   1. Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
   2. University of Chinese Academy of Sciences, Beijing, China

   Contribution

   Validation

   Competing interests

   No competing interests declared

3. Zhuo-Cong Li

   1. Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
   2. University of Chinese Academy of Sciences, Beijing, China

   Contribution

   Methodology

   Competing interests

   No competing interests declared

4. Bao-Jie Cui

   1. Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
   2. College of Fisheries and Life Science, Dalian Ocean University, Dalian, China

   Contribution

   Validation

   Competing interests

   No competing interests declared

5. Yang-Yang Wang

   1. Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
   2. University of Chinese Academy of Sciences, Beijing, China

   Contribution

   Investigation

   Competing interests

   No competing interests declared

6. Ke-Jia Han

   1. Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
   2. College of Fisheries and Life Science, Dalian Ocean University, Dalian, China

   Contribution

   Methodology

   Competing interests

   No competing interests declared

7. Xiao Xu

   1. Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
   2. College of Fisheries and Life Science, Dalian Ocean University, Dalian, China

   Contribution

   Investigation

   Competing interests

   No competing interests declared

8. Chu-Jing Zhou

   1. Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
   2. College of Fisheries and Life Science, Dalian Ocean University, Dalian, China

   Contribution

   Software

   Competing interests

   No competing interests declared

9. Xiao-Yu Zhou

   1. Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
   2. University of Chinese Academy of Sciences, Beijing, China

   Contribution

   Methodology

   Competing interests

   No competing interests declared

10. Yue Wu

    1. Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
    2. University of Chinese Academy of Sciences, Beijing, China

    Contribution

    Software

    Competing interests

    No competing interests declared

11. Na Xu

    1. Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
    2. University of Chinese Academy of Sciences, Beijing, China

    Contribution

    Investigation

    Competing interests

    No competing interests declared

12. Xiao-Li Yang

    1. Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
    2. University of Chinese Academy of Sciences, Beijing, China

    Contribution

    Methodology

    Competing interests

    No competing interests declared

13. Dan-Dan Chen

    1. Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
    2. University of Chinese Academy of Sciences, Beijing, China

    Contribution

    Software, Funding acquisition

    Competing interests

    No competing interests declared

14. Xiyin Li

    1. Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
    2. University of Chinese Academy of Sciences, Beijing, China
    3. State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Wuhan, China
    4. Key Laboratory of Aquaculture Disease Control, Ministry of Agriculture, Wuhan, China

    Contribution

    Supervision

    Competing interests

    No competing interests declared

15. Li Zhou

    1. Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
    2. University of Chinese Academy of Sciences, Beijing, China
    3. State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Wuhan, China
    4. Key Laboratory of Aquaculture Disease Control, Ministry of Agriculture, Wuhan, China

    Contribution

    Supervision

    Competing interests

    No competing interests declared

16. Shun Li

    1. Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China
    2. University of Chinese Academy of Sciences, Beijing, China
    3. State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Wuhan, China
    4. Key Laboratory of Aquaculture Disease Control, Ministry of Agriculture, Wuhan, China
    5. Laboratory for Marine Biology and Biotechnology, Qingdao Marine Science and Technology Center, Qingdao, China

    Contribution

    Conceptualization, Supervision, Funding acquisition, Writing – review and editing

    For correspondence

    bob@ihb.ac.cn

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-3629-9900

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