Innate Antiviral Host Defense Attenuates TGF-β Function through IRF3-Mediated Suppression of Smad Signaling

Xu, Pinglong; Bailey-Bucktrout, Samantha L.; Xi, Ying; Xu, Daqi; Du, Dan; Zhang, Qian; Xiang, Weiwen; Liu, Jianming; Melton, Andrew C.; Sheppard, Dean; Chapman, Harold A.; Bluestone, Jeffrey A.; Derynck, Rik

doi:10.1016/j.molcel.2014.11.027

Cited by 64 publications

(76 citation statements)

References 65 publications

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“…As shown in Figure 1J, H 2 O 2 treatment reduced IRF3 Ser396 phosphorylation and dimerization in response to Sendai virus (SeV) infection, thereby supporting an inhibitory function of Mst1 in virus-induced IRF3 regulation. Consistently, we observed a lower expression of antiviral products such as well-defined ISGs, including IFIT1 and ISG15 (Akira et al 2006;Xu et al 2014), in response to combined treatment of SeV infection and H 2 O 2 (Fig. 1K).…”

Section: Mst1 Attenuates Cytosolic Rna/dna Sensingsupporting

confidence: 79%

“…Expression plasmids encoding Flag-, Myc-, HA-, or eGFP-tagged human TBK1, IRF3, IRF3 5SD, caRIG-I, MAVS, STING, IKKε, Smad3, and the IRF3/7-responsive reporters IFNβ_Luc and 5xIS-RE_Luc have been described (Xu et al 2014). ORFs of Mst1-4 and YSK1 were obtained from the Invitrogen ORF Lite Clone Collection cDNA library by PCR, and Flag-, Myc-, or HA-tagged mouse Mst1 was constructed on pRK5 mammal expression vector.…”

Section: Expression Plasmids Reagents Antibodies and Micementioning

confidence: 99%

“…Xtremegene HP (Roche) or Polythylenimine (PEI, Polyscience) transfection reagents was used for transfection. Infection of SeV, VSV, and HSV-1 was as described (Xu et al 2014).…”

Section: Cell Culture Transfections and Infectionsmentioning

confidence: 99%

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Mst1 shuts off cytosolic antiviral defense through IRF3 phosphorylation

Meng

Zhou

et al. 2016

Genes Dev.

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Cytosolic RNA/DNA sensing elicits primary defense against viral pathogens. Interferon regulatory factor 3 (IRF3), a key signal mediator/transcriptional factor of the antiviral-sensing pathway, is indispensible for interferon production and antiviral defense. However, how the status of IRF3 activation is controlled remains elusive. Through a functional screen of the human kinome, we found that mammalian sterile 20-like kinase 1 (Mst1), but not Mst2, profoundly inhibited cytosolic nucleic acid sensing. Mst1 associated with IRF3 and directly phosphorylated IRF3 at Thr75 and Thr253. This Mst1-mediated phosphorylation abolished activated IRF3 homodimerization, its occupancy on chromatin, and subsequent IRF3-mediated transcriptional responses. In addition, Mst1 also impeded virus-induced activation of TANK-binding kinase 1 (TBK1), further attenuating IRF3 activation. As a result, Mst1 depletion or ablation enabled an enhanced antiviral response and defense in cells and mice. Therefore, the identification of Mst1 as a novel physiological negative regulator of IRF3 activation provides mechanistic insights into innate antiviral defense and potential antiviral prevention strategies.

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Section: Mst1 Attenuates Cytosolic Rna/dna Sensingsupporting

confidence: 79%

Section: Expression Plasmids Reagents Antibodies and Micementioning

confidence: 99%

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Mst1 shuts off cytosolic antiviral defense through IRF3 phosphorylation

Meng

Zhou

et al. 2016

Genes Dev.

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“…Interferon regulatory factor 3 (IRF3), activated by innate antiviral signaling, suppresses TGF‐ β ‐induced growth inhibition and gene regulation through interaction with Smad3 (Xu et al . ). Poly(I:C) can activate IRF3 in PAECs (Yang et al .…”

Section: Discussionmentioning

confidence: 97%

Characterization of miRNAs involved in response to poly(I:C) in porcine airway epithelial cells

Wang

Han

et al. 2016

Animal Genetics

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MicroRNAs (miRNA) have been implicated in a variety of pathological conditions including infectious diseases. Knowledge of the miRNAs affected by poly(I:C), a synthetic analog of viral double-stranded RNA, in porcine airway epithelial cells (PAECs) contributes to understanding the mechanisms of swine viral respiratory diseases, which bring enormous economic loss worldwide every year. In this study, we used high throughput sequencing to profile miRNA expression in PAECs treated with poly(I:C) as compared to the untreated control. This approach revealed 23 differentially expressed miRNAs (DEMs), five of which have not been implicated in viral infection before. Nineteen of the 23 miRNAs were down-regulated including members of the miR-17-92 cluster, a well-known polycistronic oncomir and extensively involved in viral infection in humans. Target genes of DEMs, predicted using bioinformatic methods and validated by luciferase reporter analysis on two representative DEMs, were significantly enriched in several pathways including transforming growth factor-β signaling. A large quantity of sequence variations (isomiRs) were found including a substitution at position 5, which was verified to redirect miRNAs to a new spectrum of targets by luciferase reporter assay together with bioinformatics analysis. Twelve novel porcine miRNAs conserved in other species were identified by homology analysis together with cloning verification. Furthermore, the expression analysis revealed the potential importance of three novel miRNAs in porcine immune response to viruses. Overall, our data contribute to clarifying the mechanisms underlying the host immune response against respiratory viruses in pigs, and enriches the repertoire of porcine miRNAs.

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“…Furthermore, MSCs impair the maturation, cytokine production and T cell stimulatory capacity of dendritic cells. In addition, MSCs suppress the proliferation and antibody production of B cells, inhibit the proliferation and cytokine secretion of CD4 + T lymphocyte subsets, and promote the expansion of regulatory T cell populations (46). …”

Section: Discussionmentioning

confidence: 99%

Safety and therapeutic effect of mesenchymal stem cell infusion on moderate to severe ulcerative colitis

Hu¹,

Zhao²,

Zhang³

et al. 2016

Experimental and Therapeutic Medicine

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One of the primary targets of the clinical treatment of ulcerative colitis (UC) is to repair the damaged colonic mucosa. Mesenchymal stem cells (MSCs) have therapeutic potential in regenerative medicine due to their differentiation capacity and their secretion of numerous bioactive molecules. The present study describes a clinical trial (trial registration no. NCT01221428) investigating the safety and therapeutic effect of MSCs derived from human umbilical cord on moderate to severe UC. Thirty-four patients with UC were included in group I and treated with MSC infusion in addition to the base treatment, and thirty-six patients were in group II and treated with normal saline in addition to the base treatment. One month after therapy, 30/36 patients in group I showed good response, and diffuse and deep ulcer formation and severe inflammatory mucosa were improved markedly. During the follow up, the median Mayo score and histology score in group I were decreased while IBDQ scores were significantly improved compared with before treatment and group II (P<0.05). Compared with group II, there were no evident adverse reactions after MSC infusion in any of the patients in group I, and no chronic side effects or lingering effects appeared during the follow-up period. In conclusion, MSC infusion might be a useful and safe therapy for treating UC.

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Innate Antiviral Host Defense Attenuates TGF-β Function through IRF3-Mediated Suppression of Smad Signaling

Cited by 64 publications

References 65 publications

Mst1 shuts off cytosolic antiviral defense through IRF3 phosphorylation

Mst1 shuts off cytosolic antiviral defense through IRF3 phosphorylation

Characterization of miRNAs involved in response to poly(I:C) in porcine airway epithelial cells

Safety and therapeutic effect of mesenchymal stem cell infusion on moderate to severe ulcerative colitis

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