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Calcineurin subunit B upregulates ?-interferon production by phosphorylation of interferon regulatory factor 3 via Toll-like receptor 4.

ABSTRACT: Toll-like receptors (TLRs) function as pattern-reorganization receptors in mammals and play an essential role in innate immunity. After recognizing certain ligands, TLRs activate a cascade of signal pathways to establish a guard environment. For the first time, we report that in vitro treatment with recombinant calcineurin subunit B (CNB) upregulated several TLR-related genes. Calcineurin subunit B interacted with the ectodomain of TLR4 in vitro. On further investigation, phosphorylation of interferon regulatory factor 3 and degradation of I?B-? were observed by CNB stimulation. In addition to pro-inflammatory cytokines, transcription and production of ?-interferon were also enhanced after CNB stimulation. Thus, CNB could be further explored as a cancer and virus immunotherapy drug.

SUBMITTER: Wang X

PROVIDER: S-EPMC7713623 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Calcineurin subunit B upregulates β-interferon production by phosphorylation of interferon regulatory factor 3 via Toll-like receptor 4.

Wang Xinyu X Li Li L Huang Yi Y Wei Qun Q

Cancer science 20120106 3

Toll-like receptors (TLRs) function as pattern-reorganization receptors in mammals and play an essential role in innate immunity. After recognizing certain ligands, TLRs activate a cascade of signal pathways to establish a guard environment. For the first time, we report that in vitro treatment with recombinant calcineurin subunit B (CNB) upregulated several TLR-related genes. Calcineurin subunit B interacted with the ectodomain of TLR4 in vitro. On further investigation, phosphorylation of inte ...[more]

PMID: 22118374

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Project description:The innate immune response is vital for host defense and must be tightly controlled, but the mechanisms responsible for its negative regulation are not fully understood. The cell growth-regulating nucleolar protein LYAR was found to promote replication of multiple viruses in our previous study. Here, we report that LYAR acts as a negative regulator of innate immune responses. We found that LYAR expression is induced by beta interferon (IFN-?) during virus infection. Further studies showed that LYAR interacts with phosphorylated IFN regulatory factor 3 (IRF3) to impede the DNA binding capacity of IRF3, thereby suppressing the transcription of IFN-? and downstream IFN-stimulated genes (ISGs). In addition, LYAR inhibits nuclear factor-?B (NF-?B)-mediated expression of proinflammatory cytokines. In summary, our study reveals the mechanism of LYAR in modulating IFN-?-mediated innate immune responses by targeting phosphorylated IRF3, which not only helps us to better understand the mechanisms of LYAR-regulated virus replication but also uncovers a novel role of LYAR in host innate immunity.IMPORTANCE Type I interferon (IFN-I) plays a critical role in the antiviral innate immune responses that protect the host against virus infection. The negative regulators of IFN-I are important not only for fine-tuning the antiviral responses to pathogens but also for preventing excessive inflammation. Identification of negative regulators and study of their modulation in innate immune responses will lead to new strategies for the control of both viral and inflammatory diseases. Here, we report for the first time that the cell growth-regulating nucleolar protein LYAR behaves as a repressor of host innate immune responses. We demonstrate that LYAR negatively regulates IFN-?-mediated immune responses by inhibiting the DNA binding ability of IFN regulatory factor 3 (IRF3). Our study reveals a common mechanism of LYAR in promoting different virus replication events and improves our knowledge of host negative regulation of innate immune responses.

Dataset Information

Calcineurin subunit B upregulates ?-interferon production by phosphorylation of interferon regulatory factor 3 via Toll-like receptor 4.

Publications

Calcineurin subunit B upregulates β-interferon production by phosphorylation of interferon regulatory factor 3 via Toll-like receptor 4.

Similar Datasets

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