scholarly journals Zinc finger protein ZFP36L1 inhibits influenza A virus through translational repression by targeting HA, M and NS RNA transcripts

2020 ◽  
Author(s):  
Ren-Jye Lin ◽  
Chih-Heng Huang ◽  
Ping-Cheng Liu ◽  
I-Chieh Lin ◽  
Yu-Ling Huang ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Zinc Finger ◽  
Influenza A ◽  
Rna Binding ◽  
Zinc Finger Protein ◽  
Protein Translation ◽  
Translational Repression ◽  
Ns1 Protein ◽  
Innate Defense ◽  
Finger Protein

Abstract ZFP36L1, a CCCH-type zinc finger protein, is an RNA-binding protein that participates in controlling cellular mRNA abundance and turnover by posttranscriptional regulation. Here, we demonstrated that ZFP36L1 has an important role in host defense against influenza A virus (IAV) infection. Overexpression of ZFP36L1 reduced IAV replication via translational repression of HA, M and NS RNA segment transcripts. IAV infection upregulated cellular ZFP36L1 expression, and endogenous ZFP36L1 knockdown significantly enhanced IAV replication. ZFP36L1 directly binds to IAV NS1 mRNA in the cytoplasm and blocks the expression and function of NS1 protein. Mutation of CCCH-type zinc finger domains of ZFP36L1 lost its antiviral potential and NS1 mRNA binding. Thus, ZFP36L1 can act as a host innate defense by targeting HA, M and NS mRNA transcripts to suppress viral protein translation.

Understanding RNA Binding by the Nonclassical Zinc Finger Protein CPSF30, a Key Factor in Polyadenylation during Pre-mRNA Processing

Biochemistry ◽  
2021 ◽  
Author(s):  
Jordan D. Pritts ◽  
Abdulafeez A. Oluyadi ◽  
Weiliang Huang ◽  
Geoffrey D. Shimberg ◽  
Maureen A. Kane ◽  
...  
Keyword(s):  
Zinc Finger ◽  
Rna Binding ◽  
Zinc Finger Protein ◽  
Mrna Processing ◽  
Finger Protein ◽  
Key Factor

Zinc finger protein ZFP36L1 inhibits flavivirus infection by both 5′-3′ XRN1 and 3′-5′ RNA-exosome RNA decay pathways.

2021 ◽  
Author(s):  
Han Chiu ◽  
Hsin-Ping Chiu ◽  
Han-Pang Yu ◽  
Li-Hsiung Lin ◽  
Zih-Ping Chen ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Dengue Virus ◽  
Zinc Finger ◽  
Rna Binding ◽  
Zinc Finger Protein ◽  
Viral Rna ◽  
Rna Decay ◽  
Finger Protein ◽  
Zinc Finger Motifs ◽  
Rna Exosome

Zinc-finger protein 36, CCCH type-like 1 (ZFP36L1), containing tandem CCCH-type zinc-finger motifs with an RNA-binding property, plays an important role in cellular RNA metabolism mainly via RNA decay pathways. Recently, we demonstrated that human ZFP36L1 has potent antiviral activity against influenza A virus infection. However, its role in the host defense response against flaviviruses has not been addressed. Here, we demonstrate that ZFP36L1 functions as a host innate defender against flaviviruses, including Japanese encephalitis virus (JEV) and dengue virus (DENV). Overexpression of ZFP36L1 reduced JEV and DENV infection, and ZFP36L1 knockdown enhanced viral replication. ZFP36L1 destabilized the JEV genome by targeting and degrading viral RNA mediated by both 5′-3′ XRN1 and 3′-5′ RNA-exosome RNA decay pathways. Mutation in both zinc-finger motifs of ZFP36L1 disrupted RNA-binding and antiviral activity. Furthermore, the viral RNA sequences specifically recognized by ZFP36L1 were mapped to the 3'-untranslated region of the JEV genome with the AU-rich element (AUUUA) motif. We extend the function of ZFP36L1 to host antiviral defense by directly binding and destabilizing the viral genome via recruiting cellular mRNA decay machineries. Importance Cellular RNA-binding proteins are among the first lines of defense against various viruses, particularly RNA viruses. ZFP36L1 belongs to the CCCH-type zinc-finger protein family and has RNA-binding activity; it has been reported to directly bind to the AU-rich elements (AREs) of a subset of cellular mRNAs and then lead to mRNA decay by recruiting mRNA degrading enzymes. However, the antiviral potential of ZFP36L1 against flaviviruses has not yet been fully demonstrated. Here, we reveal the antiviral potential of human ZFP36L1 against Japanese encephalitis virus (JEV) and dengue virus (DENV). ZFP36L1 specifically targeted the ARE motif within viral RNA and triggered the degradation of viral RNA transcripts via cellular degrading enzymes, 5′-3′ XRN1 and 3′-5′ RNA exosome. These findings provide mechanistic insights into how human ZFP36L1 serves as a host antiviral factor to restrict flavivirus replication.

scholarly journals The accumulation of influenza A virus segment 7 spliced mRNAs is regulated by the NS1 protein

2012 ◽  
Vol 93 (1) ◽  
pp. 113-118 ◽  
Author(s):  
Nicole C. Robb ◽  
Ervin Fodor
Keyword(s):  
Influenza Virus ◽  
Viral Infection ◽  
Influenza A Virus ◽  
Influenza A ◽  
Rna Binding ◽  
Mrna Splicing ◽  
Ns1 Protein ◽  
Binding Ability ◽  
Alternatively Spliced ◽  
Transcription And Replication

The influenza A virus M1 mRNA is alternatively spliced to produce M2 mRNA, mRNA3, and in some cases, M4 mRNA. Splicing of influenza mRNAs is carried out by the cellular splicing machinery and is thought to be regulated, as both spliced and unspliced mRNAs encode proteins. In this study, we used radioactively labelled primers to investigate the accumulation of spliced and unspliced M segment mRNAs in viral infection and ribonucleoprotein (RNP) reconstitution assays in which only the minimal components required for transcription and replication to occur were expressed. We found that co-expression of the viral NS1 protein in an RNP reconstitution assay altered the accumulation of spliced mRNAs compared with when it was absent, and that this activity was dependent on the RNA-binding ability of NS1. These findings suggest that the NS1 protein plays a role in the regulation of splicing of influenza virus M1 mRNA.

scholarly journals Functional Replacement of the Carboxy-Terminal Two-Thirds of the Influenza A Virus NS1 Protein with Short Heterologous Dimerization Domains

2002 ◽  
Vol 76 (24) ◽  
pp. 12951-12962 ◽  
Author(s):  
Xiuyan Wang ◽  
Christopher F. Basler ◽  
Bryan R. G. Williams ◽  
Robert H. Silverman ◽  
Peter Palese ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Influenza A Virus ◽  
Influenza A ◽  
Rna Binding ◽  
Influenza Viruses ◽  
Ns1 Protein ◽  
Wild Type ◽  
Dimerization Domain ◽  
Carboxy Terminal

ABSTRACT The NS1 protein of influenza A/WSN/33 virus is a 230-amino-acid-long protein which functions as an interferon alpha/beta (IFN-α/β) antagonist by preventing the synthesis of IFN during viral infection. In tissue culture, the IFN inhibitory function of the NS1 protein has been mapped to the RNA binding domain, the first 73 amino acids. Nevertheless, influenza viruses expressing carboxy-terminally truncated NS1 proteins are attenuated in mice. Dimerization of the NS1 protein has previously been shown to be essential for its RNA binding activity. We have explored the ability of heterologous dimerization domains to functionally substitute in vivo for the carboxy-terminal domains of the NS1 protein. Recombinant influenza viruses were generated that expressed truncated NS1 proteins of 126 amino acids, fused to 28 or 24 amino acids derived from the dimerization domains of either the Saccharomyces cerevisiae PUT3 or the Drosophila melanogaster Ncd (DmNcd) proteins. These viruses regained virulence and lethality in mice. Moreover, a recombinant influenza virus expressing only the first 73 amino acids of the NS1 protein was able to replicate in mice lacking three IFN-regulated antiviral enzymes, PKR, RNaseL, and Mx, but not in wild-type (Mx-deficient) mice, suggesting that the attenuation was mainly due to an inability to inhibit the IFN system. Remarkably, a virus with an NS1 truncated at amino acid 73 but fused to the dimerization domain of DmNcd replicated and was also highly pathogenic in wild-type mice. These results suggest that the main biological function of the carboxy-terminal region of the NS1 protein of influenza A virus is the enhancement of its IFN antagonist properties by stabilizing the NS1 dimeric structure.

scholarly journals The Tristetraprolin Family of RNA-Binding Proteins in Cancer: Progress and Future Prospects

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1539 ◽  
Author(s):  
Yogesh Saini ◽  
Jian Chen ◽  
Sonika Patial
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Zinc Finger ◽  
Binding Proteins ◽  
Rna Binding ◽  
Zinc Finger Protein ◽  
Rna Binding Proteins ◽  
Regulation Of Gene Expression ◽  
Finger Protein ◽  
Post Transcriptional Regulation

Post-transcriptional regulation of gene expression plays a key role in cellular proliferation, differentiation, migration, and apoptosis. Increasing evidence suggests dysregulated post-transcriptional gene expression as an important mechanism in the pathogenesis of cancer. The tristetraprolin family of RNA-binding proteins (RBPs), which include Zinc Finger Protein 36 (ZFP36; commonly referred to as tristetraprolin (TTP)), Zinc Finger Protein 36 like 1 (ZFP36L1), and Zinc Finger Protein 36 like 2 (ZFP36L2), play key roles in the post-transcriptional regulation of gene expression. Mechanistically, these proteins function by binding to the AU-rich elements within the 3′-untranslated regions of their target mRNAs and, in turn, increasing mRNA turnover. The TTP family RBPs are emerging as key regulators of multiple biological processes relevant to cancer and are aberrantly expressed in numerous human cancers. The TTP family RBPs have tumor-suppressive properties and are also associated with cancer prognosis, metastasis, and resistance to chemotherapy. Herein, we summarize the various hallmark molecular traits of cancers that are reported to be regulated by the TTP family RBPs. We emphasize the role of the TTP family RBPs in the regulation of trait-associated mRNA targets in relevant cancer types/cell lines. Finally, we highlight the potential of the TTP family RBPs as prognostic indicators and discuss the possibility of targeting these TTP family RBPs for therapeutic benefits.

The N-terminal residual arginine19 of influenza A virus NS1 protein is required for its nuclear localization and RNA binding

2020 ◽  
Vol 251 ◽  
pp. 108895
Author(s):  
Xingbo Wang ◽  
Lulu Lin ◽  
Yang Yu ◽  
Yan Yan ◽  
Nishant Kumar Ojha ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Nuclear Localization ◽  
Influenza A ◽  
Rna Binding ◽  
Ns1 Protein

scholarly journals Control of a neuronal morphology program by an RNA-binding zinc finger protein, Unkempt

2015 ◽  
Vol 29 (5) ◽  
pp. 501-512 ◽  
Author(s):  
Jernej Murn ◽  
Kathi Zarnack ◽  
Yawei J. Yang ◽  
Omer Durak ◽  
Elisabeth A. Murphy ◽  
...  
Keyword(s):  
Zinc Finger ◽  
Rna Binding ◽  
Zinc Finger Protein ◽  
Neuronal Morphology ◽  
Finger Protein

scholarly journals Robust Lys63-Linked Ubiquitination of RIG-I Promotes Cytokine Eruption in Early Influenza B Virus Infection

2016 ◽  
Vol 90 (14) ◽  
pp. 6263-6275 ◽  
Author(s):  
Jingwen Jiang ◽  
Jing Li ◽  
Wenhui Fan ◽  
Weinan Zheng ◽  
Meng Yu ◽  
...  
Keyword(s):  
Virus Infection ◽  
Influenza A Virus ◽  
Influenza A ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Influenza B Virus ◽  
Influenza B ◽  
Type I ◽  
Ns1 Protein ◽  
B Virus

ABSTRACTInfluenza A and B virus infections both cause a host innate immunity response. Here, we report that the robust production of type I and III interferons (IFNs), IFN-stimulated genes, and proinflammatory factors can be induced by influenza B virus rather than influenza A virus infection in alveolar epithelial (A549) cells during early infection. This response is mainly dependent on the retinoic acid-inducible gene I (RIG-I)-mediated signaling pathway. Infection by influenza B virus promotes intense Lys63-linked ubiquitination of RIG-I, resulting in cytokine eruption. It is known that the influenza A virus NS1 protein (NS1-A) interacts with RIG-I and TRIM25 to suppress the activation of RIG-I-mediated signaling. However, the present results indicate that the influenza B virus NS1 protein (NS1-B) is unable to interact with RIG-I but engages in the formation of a RIG-I/TRIM25/NS1-B ternary complex. Furthermore, we demonstrate that the N-terminal RNA-binding domain (RBD) of NS1-B is responsible for interaction with TRIM25 and that this interaction blocks the inhibitory effect of the NS1-B C-terminal effector domain (TED) on RIG-I ubiquitination. Our findings reveal a novel mechanism for the host cytokine response to influenza B virus infection through regulatory interplay between host and viral proteins.IMPORTANCEInfluenza B virus generally causes local mild epidemics but is occasionally lethal to individuals. Existing studies describe the broad characteristics of influenza B virus epidemiology and pathology. However, to develop better prevention and treatments for the disease, determining the concrete molecular mechanisms of pathogenesis becomes pivotal to understand how the host reacts to the challenge of influenza B virus. Thus, we aimed to characterize the host innate immune response to influenza B virus infection. Here, we show that vigorous Lys63-linked ubiquitination of RIG-I and cytokine eruption dependent on RIG-I-mediated signal transduction are induced by virus infection. Additionally, TRIM25 positively regulates RIG-I-mediated signaling by ablating the inhibitory function of NS1-B on RIG-I ubiquitination.

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