Inducible TAP1 Negatively Regulates the Antiviral Innate Immune Response by Targeting the TAK1 Complex

Xia, Zhangchuan; Xu, Gang; Yang, Xiaodan; Peng, Nanfang; Zuo, Qi; Zhu, Shengli; Hao, Hua; Zhu, Ying

doi:10.4049/jimmunol.1601588

Cited by 24 publications

(22 citation statements)

References 68 publications

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“…A549 IFNAR1 KO cell line was generated by CRISPR-Cas9 system described before[37]. The following oligonucleotides specific targeting the IFNAR1 gene were used:…”

Section: Methodsmentioning

confidence: 99%

Inducible LGALS3BP/90K activates antiviral innate immune responses by targeting TRAF6 and TRAF3 complex

Xia

Deng

et al. 2019

PLoS Pathog

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The galectin 3 binding protein (LGALS3BP, also known as 90K) is a ubiquitous multifunctional secreted glycoprotein originally identified in cancer progression. It remains unclear how 90K functions in innate immunity during viral infections. In this study, we found that viral infections resulted in elevated levels of 90K. Further studies demonstrated that 90K expression suppressed virus replication by inducing IFN and pro-inflammatory cytokine production. Upon investigating the mechanisms behind this event, we found that 90K functions as a scaffold/adaptor protein to interact with TRAF6, TRAF3, TAK1 and TBK1. Furthermore, 90K enhanced TRAF6 and TRAF3 ubiquitination and served as a specific ubiquitination substrate of TRAF6, leading to transcription factor NF-κB, IRF3 and IRF7 translocation from the cytoplasm to the nucleus. Conclusions: 90K is a virus-induced protein capable of binding with the TRAF6 and TRAF3 complex, leading to IFN and pro-inflammatory production.

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“…A549 IFNAR1 KO cell line was generated by CRISPR-Cas9 system described before[37]. The following oligonucleotides specific targeting the IFNAR1 gene were used:…”

Section: Methodsmentioning

confidence: 99%

Inducible LGALS3BP/90K activates antiviral innate immune responses by targeting TRAF6 and TRAF3 complex

Xia

Deng

et al. 2019

PLoS Pathog

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“…LYAR-overexpressed or LYAR-KO HEK293T cells were infected with VSV-GFP or Sev at an MOI of 1.0. Viral supernatants were harvested at the indicated time points postinfection, and plaque assays were performed on Vero cells to titrate the VSV titer as described previously (50). To detect the Sev virus titer, Vero cells were seeded in 96-well plates before Sev virus infection.…”

Section: Methodsmentioning

confidence: 99%

LYAR Suppresses Beta Interferon Induction by Targeting Phosphorylated Interferon Regulatory Factor 3

Yang

Liu

Cheng

et al. 2019

J Virol

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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-β) 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-β and downstream IFN-stimulated genes (ISGs). In addition, LYAR inhibits nuclear factor-κB (NF-κB)-mediated expression of proinflammatory cytokines. In summary, our study reveals the mechanism of LYAR in modulating IFN-β-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-β-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.

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“…Consistent with this, Huang et al reported the transcription factor peroxisome proliferator-activated receptor gamma (PPAR-γ) as a negative regulator of inflammation during IAV infection in alveolar macrophages (AM) as PPAR-γ deficiency in AM enhanced pulmonary inflammation and host morbidity [ 216 ]. Similarly, transporter 1, ATP-binding cassette, subfamily B (TAP1) is shown to be upregulated upon IAV infection and inhibit NF-κB-mediated proinflammatory cytokine production by targeting the TAK1 complex [ 217 ]. Furthermore, the NLR family protein NLRX1 is also reported to attenuate IAV induced inflammation by meddling with the RIG-I-MAVS signaling pathway and TRAF6 ubiquitin ligase, an essential component of antiviral TLR signaling [ 218 ].…”

Section: Negative Host Regulatorsmentioning

confidence: 99%

Innate Immune Sensing of Influenza A Virus

Malik

Zhou

2020

Viruses

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Influenza virus infection triggers host innate immune response by stimulating various pattern recognition receptors (PRRs). Activation of these PRRs leads to the activation of a plethora of signaling pathways, resulting in the production of interferon (IFN) and proinflammatory cytokines, followed by the expression of interferon-stimulated genes (ISGs), the recruitment of innate immune cells, or the activation of programmed cell death. All these antiviral approaches collectively restrict viral replication inside the host. However, influenza virus also engages in multiple mechanisms to subvert the innate immune responses. In this review, we discuss the role of PRRs such as Toll-like receptors (TLRs), Retinoic acid-inducible gene I (RIG-I), NOD-, LRR-, pyrin domain-containing protein 3 (NLRP3), and Z-DNA binding protein 1 (ZBP1) in sensing and restricting influenza viral infection. Further, we also discuss the mechanisms influenza virus utilizes, especially the role of viral non-structure proteins NS1, PB1-F2, and PA-X, to evade the host innate immune responses.

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Inducible TAP1 Negatively Regulates the Antiviral Innate Immune Response by Targeting the TAK1 Complex

Cited by 24 publications

References 68 publications

Inducible LGALS3BP/90K activates antiviral innate immune responses by targeting TRAF6 and TRAF3 complex

Inducible LGALS3BP/90K activates antiviral innate immune responses by targeting TRAF6 and TRAF3 complex

LYAR Suppresses Beta Interferon Induction by Targeting Phosphorylated Interferon Regulatory Factor 3

Innate Immune Sensing of Influenza A Virus

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