LncRNA IFITM4P regulates host antiviral responses by acting as a ceRNA

2021 ◽  
Author(s):  
Meng Xiao ◽  
Yuhai Chen ◽  
Song Wang ◽  
Shasha Liu ◽  
Kul Raj Rai ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Viral Infection ◽  
Noncoding Rna ◽  
Transmembrane Protein ◽  
Family Members ◽  
Ectopic Expression ◽  
Antiviral Immunity ◽  
Mrna Levels ◽  
Antiviral Responses ◽  
Innate Antiviral Immunity

Long noncoding RNAs (lncRNAs) are involved in numerous cellular processes. Increasing evidence suggests that some lncRNAs function in immunity through various complex mechanisms. However, implication of a large fraction of lncRNAs in antiviral innate immunity remains uncharacterized. Here, we identified a lncRNA called lncRNA IFITM4P that was transcribed from interferon induced transmembrane protein 4 pseudogene (IFITM4P) , a pseudogene belonging to interferon induced transmembrane protein (IFITM) family. We found that expression of lncRNA IFITM4P was significantly induced by infection with several viruses including influenza A virus (IAV). Importantly, lncRNA IFITM4P acted as a positive regulator of innate antiviral immunity. Ectopic expression of lncRNA IFITM4P significantly suppressed IAV replication in vitro , whereas IFITM4P deficiency promoted the viral production. We further observed that expression of lncRNA IFITM4P was up-regulated by interferon (IFN) signaling during viral infection, and altering the expression of this lncRNA had significant effects on the mRNA levels of several IFITM family members including IFITM1, IFITM2 and IFITM3. Moreover, it was identified that lncRNA IFITM4P was a target of miR-24-3p that represses mRNA of IFITM1, IFITM2 and IFITM3. The experiments demonstrated that lncRNA IFITM4P was able to cross-regulate the expression of IFITM family members as a competing endogenous RNA (ceRNA), leading to increased stability of these IFITM mRNAs. Together, our results reveal that lncRNA IFITM4P, as a ceRNA, is involved in innate immunity against viral infection through the lncRNA IFITM4P-miR-24-3p- IFITM1/2/3 regulatory network. IMPORTANCE LncRNAs play important roles in various biological processes, but their involvement in host antiviral responses remains largely unknown. In this study, we revealed that the pseudogene IFITM4P belonging to IFITM family can transcribe a functional long noncoding RNA termed lncRNA IFITM4P. Importantly, results showed that lncRNA IFITM4P was involved in innate antiviral immunity, which resembles some interferon-stimulated genes (ISGs). Furthermore, lncRNA IFITM4P was identified as a target of miR-24-3p and acts as a ceRNA to inhibit the replication of IAV through regulating the mRNA levels of IFITM1, IFITM2 and IFITM3. These data provide a new insight into the role of a previously uncharacterized lncRNA encoded by a pseudogene in the host antiviral response, and a better understanding of the IFITM antiviral network.

scholarly journals USP1–UAF1 deubiquitinase complex stabilizes TBK1 and enhances antiviral responses

2017 ◽  
Vol 214 (12) ◽  
pp. 3553-3563 ◽  
Author(s):  
Zhongxia Yu ◽  
Hui Song ◽  
Mutian Jia ◽  
Jintao Zhang ◽  
Wenwen Wang ◽  
...  
Keyword(s):  
Viral Infection ◽  
Degradation Process ◽  
Viral Diseases ◽  
Immune Homeostasis ◽  
Regulatory Factor ◽  
Antiviral Responses ◽  
Innate Antiviral Immunity ◽  
Irf3 Activation

Optimal activation of TANK-binding kinase 1 (TBK1) is crucial for initiation of innate antiviral immunity and maintenance of immune homeostasis. Although several E3 ubiquitin ligases have been reported to regulate TBK1 activation by mediating its polyubiquitination, the functions of deubiquitinase on TBK1 activity remain largely unclear. Here, we identified a deubiquitinase complex, which is formed by ubiquitin specific peptidase 1 (USP1) and USP1-associated factor 1 (UAF1), as a viral infection–induced physiological enhancer of TBK1 expression. USP1–UAF1 complex enhanced TLR3/4 and RIG-I–induced IFN regulatory factor 3 (IRF3) activation and subsequent IFN-β secretion. Mechanistically, USP1 and UAF1 bound to TBK1, removed its K48-linked polyubiquitination, and then reversed the degradation process of TBK1. Furthermore, we found that ML323, a specific USP1–UAF1 inhibitor, attenuated IFN-β expression and enhanced viral replication both in vitro and in vivo. Therefore, our results outline a novel mechanism for the control of TBK1 activity and suggest USP1–UAF1 complex as a potential target for the prevention of viral diseases.

Epigenetic regulation of frog innate immunity: Discovery of frog microRNAs associated with antiviral responses and ranavirus infection using a Xenopus laevis skin epithelial-like cell line

2021 ◽  
Author(s):  
Lauren A. Todd ◽  
Maxwell P. Bui-Marinos ◽  
Barbara A. Katzenback
Keyword(s):  
Xenopus Laevis ◽  
Cell Line ◽  
Antiviral Immunity ◽  
Type I Interferons ◽  
Poly I:C ◽  
Type I ◽  
Frog Virus ◽  
Interferon Stimulated Genes ◽  
Antiviral Responses ◽  
Innate Antiviral Immunity

Epigenetic regulators such as microRNAs are emerging as conserved regulators of innate antiviral immunity in vertebrates, yet their roles in amphibian antiviral responses remain uncharacterized. We profiled changes in microRNA expressions in the Xenopus laevis skin epithelial–like cell line Xela DS2 in response to poly(I:C) – an analogue of double-stranded viral RNA and inducer of type I interferons – or frog virus 3 (FV3), an immunoevasive virus associated with amphibian mortality events. We sequenced small RNA libraries generated from untreated, poly(I:C)–treated, and FV3–infected cells. We detected 136 known X. laevis microRNAs and discovered 133 novel X. laevis microRNAs. Sixty–five microRNAs were differentially expressed in response to poly(I:C), many of which were predicted to target regulators of antiviral pathways such as cGAS–STING, RIG–I/MDA–5, TLR signaling, and type I interferon signaling, as well as products of these pathways (NF–κB–induced and interferon-stimulated genes). In contrast, only 49 microRNAs were altered by FV3 infection, fewer of which were predicted to interact with antiviral pathways. Interestingly, poly(I:C) treatment or FV3 infection downregulated transcripts encoding factors of the host microRNA biogenesis pathway. Our study is the first to suggest that host microRNAs regulate innate antiviral immunity in frogs, and sheds light on microRNA–mediated mechanisms of immunoevasion by FV3.

scholarly journals Post-transcriptional regulation of frog innate immunity: discovery of frog microRNAs associated with antiviral responses and ranavirus infection using a Xenopus laevis skin epithelial-like cell line

FACETS ◽  
2021 ◽  
Vol 6 ◽  
pp. 2058-2083
Author(s):  
Lauren A. Todd ◽  
Maxwell P. Bui-Marinos ◽  
Barbara A. Katzenback
Keyword(s):  
Xenopus Laevis ◽  
Cell Line ◽  
Antiviral Immunity ◽  
Type I Interferons ◽  
Poly I:C ◽  
Type I ◽  
Frog Virus ◽  
Interferon Stimulated Genes ◽  
Antiviral Responses ◽  
Innate Antiviral Immunity

Post-transcriptional regulators such as microRNAs are emerging as conserved regulators of innate antiviral immunity in vertebrates, yet their roles in amphibian antiviral responses remain uncharacterized. We profiled changes in microRNA expressions in the Xenopus laevis skin epithelial-like cell line Xela DS2 in response to poly(I:C)—an analogue of viral double-stranded RNA and inducer of type I interferons—or frog virus 3 (FV3), an immunoevasive virus associated with amphibian mortality events. Small RNA libraries generated from untreated, poly(I:C)-treated, and FV3-infected cells were sequenced. We detected 136 known X. laevis microRNAs and discovered 133 novel X. laevis microRNAs. Sixty-five microRNAs were differentially expressed in response to poly(I:C), many of which were predicted to target regulators of antiviral pathways such as cGAS-STING, RIG-I/MDA-5, TLR signaling, and type I interferon signaling, as well as products of these pathways (NF-ĸB-induced and interferon-stimulated genes). In contrast, only 49 microRNAs were altered by FV3 infection, fewer of which were predicted to interact with antiviral pathways. Interestingly, poly(I:C) treatment or FV3 infection downregulated transcripts encoding factors of the host microRNA biogenesis pathway. Our study is the first to suggest that host microRNAs regulate innate antiviral immunity in frogs and sheds light on microRNA-mediated mechanisms of immunoevasion by FV3.

scholarly journals Long noncoding RNA #32 contributes to antiviral responses by controlling interferon-stimulated gene expression

2016 ◽  
Vol 113 (37) ◽  
pp. 10388-10393 ◽  
Author(s):  
Hironori Nishitsuji ◽  
Saneyuki Ujino ◽  
Sachiyo Yoshio ◽  
Masaya Sugiyama ◽  
Masashi Mizokami ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Ectopic Expression ◽  
Encephalomyocarditis Virus ◽  
Type I ◽  
Antiviral Responses ◽  
Biological Phenomena ◽  
B Virus ◽  
Activating Transcription Factor ◽  
Host Antiviral Response

Despite the breadth of knowledge that exists regarding the function of long noncoding RNAs (lncRNAs) in biological phenomena, the role of lncRNAs in host antiviral responses is poorly understood. Here, we report that lncRNA#32 is associated with type I IFN signaling. The silencing of lncRNA#32 dramatically reduced the level of IFN-stimulated gene (ISG) expression, resulting in sensitivity to encephalomyocarditis virus (EMCV) infection. In contrast, the ectopic expression of lncRNA#32 significantly suppressed EMCV replication, suggesting that lncRNA#32 positively regulates the host antiviral response. We further demonstrated the suppressive function of lncRNA#32 in hepatitis B virus and hepatitis C virus infection. lncRNA#32 bound to activating transcription factor 2 (ATF2) and regulated ISG expression. Our results reveal a role for lncRNA#32 in host antiviral responses.

scholarly journals Crosstalk between Autophagy and Type I Interferon Responses in Innate Antiviral Immunity

Viruses ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 132 ◽  
Author(s):  
Yu Tian ◽  
Ming-Li Wang ◽  
Jun Zhao
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Type I Interferon ◽  
Antiviral Immunity ◽  
Type I ◽  
Viral Components ◽  
Interferon Responses ◽  
Innate Antiviral Immunity

Autophagy exhibits dual effects during viral infections, promoting the clearance of viral components and activating the immune system to produce antiviral cytokines. However, some viruses impair immune defenses by collaborating with autophagy. Mounting evidence suggests that the interaction between autophagy and innate immunity is critical to understanding the contradictory roles of autophagy. Type I interferon (IFN-I) is a crucial antiviral factor, and studies have indicated that autophagy affects IFN-I responses by regulating IFN-I and its receptors expression. Similarly, IFN-I and interferon-stimulated gene (ISG) products can harness autophagy to regulate antiviral immunity. Crosstalk between autophagy and IFN-I responses could be a vital aspect of the molecular mechanisms involving autophagy in innate antiviral immunity. This review briefly summarizes the approaches by which autophagy regulates antiviral IFN-I responses and highlights the recent advances on the mechanisms by which IFN-I and ISG products employ autophagy against viruses.

Activating E2Fs mediate transcriptional regulation of human E2F6 repressor

2006 ◽  
Vol 290 (1) ◽  
pp. C189-C199 ◽  
Author(s):  
Tarrah E. Lyons ◽  
Maysoon Salih ◽  
Balwant S. Tuana
Keyword(s):  
Cell Cycle ◽  
Binding Sites ◽  
Cell Cycle Regulation ◽  
Promoter Activity ◽  
Time Course ◽  
Family Members ◽  
Ectopic Expression ◽  
Transcriptional Level ◽  
Mrna Levels ◽  
Cycle Regulation

E2F6 is believed to repress E2F-responsive genes and therefore serve a role in cell cycle regulation. Analysis of the human E2F6 promoter region revealed the presence of two putative E2F binding sites, both of which were found to be functionally critical because deletion or mutations of these sites abolished promoter activity. Ectopic expression of E2F1 protein was found to increase E2F6 mRNA levels and significantly upregulate E2F6 promoter activity. Deletion or mutation of the putative E2F binding sites nullified the effects of E2F1 on the E2F6 promoter activity. Studies on the temporal induction of E2F family members demonstrated that the activating E2Fs, and most notably E2F1, were upregulated before E2F6 during cell cycle progression at the G1/S phase, and this coincided with the time course of induction experienced by the E2F6 promoter during the course of the cell cycle. EMSAs indicated the specific binding of nuclear complexes to the E2F6 promoter that contained E2F1-related species whose binding was specifically competed by the consensus E2F binding site. Chromatin immunoprecipitation assays with anti-E2Fs demonstrated the association of E2F family members with the E2F6 promoter in vivo. These data indicate that the expression of the E2F6 repressor is influenced at the transcriptional level by E2F family members and suggest that interplay among these transcriptional regulators, especially E2F1, may be critical for cell cycle regulation.

scholarly journals Prospects for the use of micronutrients in the treatment of coronavirus infection in patients with comorbid pathology

2020 ◽  
Vol 4 (8) ◽  
pp. 504-510
Author(s):  
O.A. Gromova ◽  
◽  
I.Yu. Torshin ◽  
A.M. Lila ◽  
A.V. Naumov ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Nutritional Status ◽  
Viral Infections ◽  
Antiviral Immunity ◽  
Glucosamine Sulfate ◽  
Cytokine Storm ◽  
Coronavirus Infection ◽  
Group B ◽  
Innate Antiviral Immunity ◽  
Russian Medical

The pandemic of the new coronavirus infection (COVID-19) has increased the need for comprehensive courses to support innate antiviral immunity. The authors’ systematic computer analysis of the texts of more than 21,000 publications devoted to coronaviruses and the infections caused by them showed that weakening the effects of the cytokine storm and compensating the patient’s chronic comorbid pathologies are fundamentally important for improving the therapy and prevention efficacy of COVID-19. In the case of COVID-19/SARS-CoV-2, it has been shown that assessment of the patient nutritional status is mandatory before applying certain approaches to the pharmacotherapy of viral infections. In this article, the authors consistently consider the most important micronutrients, which are essential for the maintenance of innate immunity and prevention of comorbid pathologies. Increasing the body’s supply of micronutrients (such as zinc, selenium, magnesium, manganese, vitamins A, C, D, E, group B, rutin, and glucosamine sulfate) helps support the activity of interferon-dependent antiviral protection, reduce chronic inflammation and reduce the effects of the cytokine storm, as well as compensate for comorbid pathologies. The effects of glucosamine sulfate, acting by inhibiting the central regulator of inflammation NF-κB, contributes to the solution of all these problems.KEYWORDS: micronutrient, nutritional status, innate immunity, glucosamine sulfate, antiviral immunity, COVID-19.FOR CITATION: Gromova O.A., Torshin I.Yu., Lila A.M. et al. Prospects for the use of micronutrients in the treatment of coronavirus infection in patients with comorbid pathology. Russian Medical Inquiry. 2020;4(8):504–510. DOI: 10.32364/2587-6821-2020-4-8-504-510.

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