Phosphorylation of TRIM28 Enhances the Expression of IFN-β and Proinflammatory Cytokines During HPAIV Infection of Human Lung Epithelial Cells

Krischuns, Tim; Günl, Franziska; Henschel, Lea; Binder, Marco; Willemsen, Joschka; Schloer, Sebastian; Rescher, Ursula; Gerlt, Vanessa; Zimmer, Gert; Nordhoff, Carolin; Ludwig, Stephan; Brunotte, Linda

doi:10.3389/fimmu.2018.02229

Cited by 73 publications

(89 citation statements)

References 75 publications

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“…The SUMOylation deficient TRIM28 can stimulate and prime IFN-α mediated innate immune defenses and restrict influenza A virus replication via a JAK1-dependent pathway [41]. Meanwhile, phosphorylation of TRIM28 leads to increased expression level of IFN-β in human lung epithelial cells during infection with highly pathogenic avian influenza viruses [42]. Knockdown of TRIM28 in A549 cells increased Sendai virus-induced IFN-α production and weakened IFN-sensitive vesicular stomatitis virus infection [30].…”

Section: Discussionmentioning

confidence: 99%

TRIM28 regulates SARS-CoV-2 cell entry by targeting ACE2

Wang

Fan

Huang

et al. 2020

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19), it binds to angiotensin-converting enzyme 2 (ACE2) to enter into human cells. The expression level of ACE2 potentially determine the susceptibility and severity of COVID-19, it is thus of importance to understand the regulatory mechanism of ACE2 expression. Tripartite motif containing 28 (TRIM28) is known to be involved in multiple processes including antiviral restriction, endogenous retrovirus latency and immune response, it is recently reported to be co-expressed with SARS-CoV-2 receptor in type II pneumocytes; however, the roles of TRIM28 in ACE2 expression and SARS-CoV-2 cell entry remain unclear. This study showed that knockdown of TRIM28 induces ACE2 expression and increases pseudotyped SARS-CoV-2 cell entry of A549 cells and primary pulmonary alveolar epithelial cells (PAEpiCs). In a co-culture model of NK cells and lung epithelial cells, our results demonstrated that NK cells inhibit TRIM28 and promote ACE2 expression in lung epithelial cells, which was partially reversed by depletion of interleukin-2 and blocking of granzyme B in the co-culture medium. Furthermore, TRIM28 knockdown enhanced interferon-γ (IFN-γ)-induced ACE2 expression through a mechanism involving upregulating IFN-γ receptor 2 (IFNGR2) in both A549 and PAEpiCs. Importantly, the upregulated ACE2 induced by TRIM28 knockdown and co-culture of NK cells was partially reversed by dexamethasone in A549 cells but not PAEpiCs. Our study identified TRIM28 as a novel regulator of ACE2 expression and SARS-CoV-2 cell entry.

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Section: Discussionmentioning

confidence: 99%

TRIM28 regulates SARS-CoV-2 cell entry by targeting ACE2

Wang

Fan

Huang

et al. 2020

Preprint

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“…PKR activation may not always be beneficial. Different strains of influenza vary in their ability to activate or evade the ISR [55,56]. Some highly pathogenic avian influenza viruses (e.g.…”

Section: Influenzamentioning

confidence: 99%

“…Some highly pathogenic avian influenza viruses (e.g. H5N1, H7N7 and H7N9) induce severe pulmonary inflammation owing to excessive production of IFN-β, interleukin (IL)-6 and IL-8 [55]. This response appears to be mediated by PKR triggering a cascade that leads to phosphorylation of TRIM28, a regulator of many immunomodulatory genes.…”

Section: Influenzamentioning

confidence: 99%

The integrated stress response in pulmonary disease

et al. 2020

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The respiratory tract and its resident immune cells face daily exposure to stress, both from without and from within. Inhaled pathogens, including severe acute respiratory syndrome coronavirus 2, and toxins from pollution trigger a cellular defence system that reduces protein synthesis to minimise viral replication or the accumulation of misfolded proteins. Simultaneously, a gene expression programme enhances antioxidant and protein folding machineries in the lung. Four kinases (PERK, PKR, GCN2 and HRI) sense a diverse range of stresses to trigger this “integrated stress response”. Here we review recent advances identifying the integrated stress response as a critical pathway in the pathogenesis of pulmonary diseases, including pneumonias, thoracic malignancy, pulmonary fibrosis and pulmonary hypertension. Understanding the integrated stress response provides novel targets for the development of therapies.

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“…Recently, a new mechanism by which MAPK p38 affects dysregulation of cytokine induction was unraveled, deciphering an IV strain-specific phosphorylation of transcriptional repressor TRIM28 (tripartite motif-containing 28) at S473, which is induced by a signaling cascade constituted of protein kinase R (PKR), p38 MAPK and MSK1 in response to RIG-I-independent sensing of viral 5 0 PPP RNA. By using chemical inhibitors as well as knockout cell lines, it was shown that MAPK p38-dependent phosphorylation of TRIM28 facilitates a functional switch leading to increased cytokine levels in cells infected with highly pathogenic viruses (Krischuns et al 2018). Besides its role in the induction of pro-inflammatory and antiviral cytokines, there have been reports of a virus-supportive function of MAPK p38 observed after inhibition of the pathway with different p38 inhibitors (Marchant et al 2010;Choi et al 2016;McCaskill et al 2017).…”

Section: Stress-induced Mapks Jnk and P38mentioning

confidence: 99%

The Two Sides of the Same Coin—Influenza Virus and Intracellular Signal Transduction

Ludwig

Hrincius

Boergeling

2019

Cold Spring Harb Perspect Med

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Cells respond to extracellular agents by activation of intracellular signaling pathways. Viruses can be regarded as such agents, leading to a firework of signaling inside the cell, primarily induced by pathogen-associated molecular patterns (PAMPs) that provoke safeguard mechanisms to defend from the invader. In the constant arms race between pathogen and cellular defense, viruses not only have evolved mechanisms to suppress or misuse supposedly antiviral signaling processes for their own benefit but also actively induce signaling to promote replication. This creates viral dependencies that may be exploited for novel strategies of antiviral intervention. Here, we will summarize the current knowledge of activation and function of influenza virus-induced signaling pathways with a focus on nuclear factor (NF)-κB signaling, mitogen-activated protein kinase cascades, and the phosphatidylinositol-3-kinase pathway. We will discuss the opportunities and drawbacks of targeting these signaling pathways for antiviral intervention.

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Phosphorylation of TRIM28 Enhances the Expression of IFN-β and Proinflammatory Cytokines During HPAIV Infection of Human Lung Epithelial Cells

Cited by 73 publications

References 75 publications

TRIM28 regulates SARS-CoV-2 cell entry by targeting ACE2

TRIM28 regulates SARS-CoV-2 cell entry by targeting ACE2

The integrated stress response in pulmonary disease

The Two Sides of the Same Coin—Influenza Virus and Intracellular Signal Transduction

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