Casein Kinase 1γ1 Inhibits the RIG-I/TLR Signaling Pathway through Phosphorylating p65 and Promoting Its Degradation

Wang, Yetao; Hu, Lei; Tong, Xiaomei; Ye, Xin

doi:10.4049/jimmunol.1302552

Cited by 23 publications

(23 citation statements)

References 33 publications

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“…Our finding that Ser 534 phosphorylation enhanced p65 half-life in multiple cell types is consistent with two previous studies that also showed the increased half-life of S536A mutants (39, 40). Note that the effects of the S534A mutation were most substantial at later time points of stimulation (for example, 8 hours after LPS injection) in both the liver and spleen, which is consistent with the finding that Ser 536 phosphorylation reduces p65 half-life.…”

Section: Discussionsupporting

confidence: 93%

“…Note that the effects of the S534A mutation were most substantial at later time points of stimulation (for example, 8 hours after LPS injection) in both the liver and spleen, which is consistent with the finding that Ser 536 phosphorylation reduces p65 half-life. Previous studies demonstrated a role for the E3 ubiquitin ligases Cullin-based ligase 2 (CUL2) and Copper metabolism MURR1 domain–containing 1 (COMMD1) in the degradation of p65 in cultured cells in response to both Ser 468 and Ser 536 phosphorylation (40, 41). Because of the mild effect of S534A phenotype in the liver, the absence of effects at some time points, and the much lower effects in tissues such as the spleen, we could not determine to what degree these cofactors regulate p65 stability in vivo.…”

Section: Discussionmentioning

confidence: 99%

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Negative regulation of NF-κB p65 activity by serine 536 phosphorylation

et al. 2016

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Nuclear factor κB (NF-κB) is a master regulator of inflammation and cell death. Whereas most of the activity of NF-κB is regulated through the inhibitor of kB (IκB) kinase (IKK)–dependent degradation of IκB, IKK also phosphorylates subunits of NF-κB. Here, we investigated the contribution of the phosphorylation of the NF-κ B subunit p65 at the IKK phosphorylation site serine 536 (Ser536) in humans, which is thought to be required for the activation and nuclear translocation of NF-κB. Through experiments with knock-in mice (S534A mice) expressing a mutant p65 with an alanine-to-serine substitution at position 534 (the murine homolog of human Ser536), we observed increased expression of NF-κ B–dependent genes after injection of mice with the inflammatory stimulus lipopolysaccharide (LPS) or exposure to gamma irradiation, and the enhanced gene expression was most pronounced at late time points. Compared to wild-type mice, S534A mice displayed increased mortality after injection with LPS. Increased NF-κ B signaling in the S534A mice was at least in part explained by the increased stability of the S534A p65 protein compared to that of the Ser534-phosphorylated wild-type protein. Together, our results suggest that Ser534 phosphorylation of p65 in mice (and, by extension, Ser536 phosphorylation of human p65) is not required for its nuclear translocation, but instead inhibits NF-κ B signaling to prevent deleterious inflammation.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Negative regulation of NF-κB p65 activity by serine 536 phosphorylation

et al. 2016

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“…It will be interesting to study how Cdc25A balances its roles in cell cycle checkpoints and the antiviral immune response. We previously reported that CK1␥1 inhibits both RIG-I and TLR signaling by phosphorylating NF-B p65 and promoting its degradation (18). Because TBK1 is the common downstream component in RLRs/TLRs as well as DNA sensors, such as AIM2, cGAS, and DDX41-mediated signaling pathways (40), we postulate that Cdc25A may also inhibit TLR-and DNA sensor-mediated innate immune responses.…”

Section: Discussionmentioning

confidence: 88%

Phosphatase Cdc25A Negatively Regulates the Antiviral Immune Response by Inhibiting TBK1 Activity

Jiao

et al. 2018

J Virol

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The phosphatase Cdc25A plays an important role in cell cycle regulation by dephosphorylating its substrates, such as cyclin-dependent kinases. In this study, we demonstrate that Cdc25A negatively regulates RIG-I-mediated antiviral signaling. We found that ectopic expression of Cdc25A in 293T cells inhibits the activation of beta interferon (IFN-β) induced by Sendai virus and poly(I·C), while knockdown of Cdc25A enhances the transcription of IFN-β stimulated by RNA virus infection. The inhibitory effect of Cdc25A on the antiviral immune response is mainly dependent on its phosphatase activity. Data from a luciferase assay indicated that Cdc25A can inhibit TBK1-mediated activation of IFN-β. Further analysis indicated that Cdc25A can interact with TBK1 and reduce the phosphorylation of TBK1 at S172, which in turn decreases the phosphorylation of its downstream substrate IRF3. Consistently, knockdown of Cdc25A upregulates the phosphorylation of both TBK1-S172 and IRF3 in Sendai virus-infected or TBK1-transfected 293T cells. In addition, we confirmed that Cdc25A can directly dephosphorylate TBK1-S172-p. These results demonstrate that Cdc25A inhibits the antiviral immune response by reducing the active form of TBK1. Using herpes simplex virus 1 (HSV-1) infection, an IFN-β reporter assay, and reverse transcription-quantitative PCR (RT-qPCR), we demonstrated that Cdc25A can also inhibit DNA virus-induced activation of IFN-β. Using a vesicular stomatitis virus (VSV) infection assay, we confirmed that Cdc25A can repress the RIG-I-like receptor (RLR)-mediated antiviral immune response and influence the antiviral status of cells. In conclusion, we demonstrate that Cdc25A negatively regulates the antiviral immune response by inhibiting TBK1 activity. The RLR-mediated antiviral immune response is critical for host defense against RNA virus infection. However, the detailed mechanism for balancing the RLR signaling pathway in host cells is not well understood. We found that the phosphatase Cdc25A negatively regulates the RNA virus-induced innate immune response. Our studies indicate that Cdc25A inhibits the RLR signaling pathway via its phosphatase activity. We demonstrated that Cdc25A reduces TBK1 activity and consequently restrains the activation of IFN-β transcription as well as the antiviral status of nearby cells. We showed that Cdc25A can also inhibit DNA virus-induced activation of IFN-β. Taken together, our findings uncover a novel function and mechanism for Cdc25A in regulating antiviral immune signaling. These findings reveal Cdc25A as an important negative regulator of antiviral immunity and demonstrate its role in maintaining host cell homeostasis following viral infection.

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“…Because these responses are vital for eliminating invading pathogens, NF-B activity must be tightly regulated to avoid an excessive immune response, and many regulators have been reported to be involved in the process. For example, as a cytoplasmic LIM protein, PDLIM1 binds to and sequesters the NF-B subunit p65, thereby inhibiting NF-B-mediated inflammatory signaling (31), and casein kinase 1␥1 (CK1␥1) phosphorylates p65 and promotes its degradation to inhibit the RIG-I/TLR signaling pathway (32). Besides, RIG-I functions as a positive regulator of NF-B signaling by interacting with NF-B1 and enhancing its translation (6).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-216a Inhibits NF-κB-Mediated Inflammatory Cytokine Production in Teleost Fish by Modulating p65

Chu

Cui

et al. 2018

Infect Immun

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Inflammation is the host self-protection mechanism to eliminate pathogen invasion. The excessive inflammatory response can result in uncontrolled inflammation, autoimmune diseases, or pathogen dissemination. Recent studies have widely shown that microRNAs (miRNAs) contribute to the regulation of inflammation in mammals by repressing gene expression at the posttranscriptional level. However, the miRNA-mediated mechanism in the inflammatory response in fish remains hazy. In the present study, the regulatory mechanism of the miR-216a-mediated inflammatory response in teleost fish was addressed. We found that the expression of miR-216a could be significantly upregulated in the miiuy croaker after challenge with and lipopolysaccharide. Bioinformatics predictions demonstrated a potential binding site of miR-216a in the 3' untranslated region of the p65 gene, and the result was further confirmed by luciferase assay. Moreover, both the mRNA and protein levels of p65 in macrophages were downregulated by miR-216a. Deletion mutant analysis of the miR-216a promoter showed that the Ap1 and Sp1 transcription factor binding sites are indispensable for the transcription of miR-216a. Further study revealed that overexpression of miR-216a suppresses inflammatory cytokine expression and negatively regulates NF-κB signaling, which inhibit an excessive inflammatory response. The collective results indicate that miR-216a plays a role as a negative regulator involved in modulating the bacterium-induced inflammatory response.

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Casein Kinase 1γ1 Inhibits the RIG-I/TLR Signaling Pathway through Phosphorylating p65 and Promoting Its Degradation

Cited by 23 publications

References 33 publications

Negative regulation of NF-κB p65 activity by serine 536 phosphorylation

Negative regulation of NF-κB p65 activity by serine 536 phosphorylation

Phosphatase Cdc25A Negatively Regulates the Antiviral Immune Response by Inhibiting TBK1 Activity

MicroRNA-216a Inhibits NF-κB-Mediated Inflammatory Cytokine Production in Teleost Fish by Modulating p65

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