Trypanosoma cruzi poly-zinc finger protein: a novel DNA/RNA-binding CCHC-zinc finger protein

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.

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Knockout of the CCCH zinc finger protein TcZC3H31 blocks Trypanosoma cruzi differentiation into the infective metacyclic form

Molecular and Biochemical Parasitology ◽

10.1016/j.molbiopara.2018.01.006 ◽

2018 ◽

Vol 221 ◽

pp. 1-9 ◽

Cited By ~ 4

Author(s):

Monica Visnieski Alcantara ◽

Rafael Luis Kessler ◽

Rosana Elisa Gonçalves Gonçalves ◽

Newmar Pinto Marliére ◽

Alessandra Aparecida Guarneri ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Zinc Finger ◽

Zinc Finger Protein ◽

Ccch Zinc Finger ◽

Finger Protein

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MCP-1 (Monocyte Chemotactic Protein-1)-induced Protein, a Recently Identified Zinc Finger Protein, Induces Adipogenesis in 3T3-L1 Pre-adipocytes without Peroxisome Proliferator-activated Receptor γ

Journal of Biological Chemistry ◽

10.1074/jbc.m109.025320 ◽

2009 ◽

Vol 284 (40) ◽

pp. 27620-27628 ◽

Cited By ~ 41

Author(s):

Craig W. Younce ◽

Asim Azfer ◽

Pappachan E. Kolattukudy

Keyword(s):

Zinc Finger ◽

Zinc Finger Protein ◽

Protein A ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Monocyte Chemotactic Protein ◽

Finger Protein ◽

Chemotactic Protein

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Nuclear transport and phosphorylation of the RNA binding Xenopus zinc finger protein XFG 5-1

Mechanisms of Development ◽

10.1016/0925-4773(92)90026-g ◽

1992 ◽

Vol 39 (1-2) ◽

pp. 63-72 ◽

Cited By ~ 9

Author(s):

Inge van Wijk ◽

Jürgen Burfeind ◽

Thomas Pieler

Keyword(s):

Zinc Finger ◽

Rna Binding ◽

Zinc Finger Protein ◽

Nuclear Transport ◽

Finger Protein

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A Trypanosoma cruzi Zinc Finger protein that controls expression of epimastigote specific genes and affects metacyclogenesis

10.1101/2020.07.07.189688 ◽

2020 ◽

Author(s):

Thais Silva Tavares ◽

Fernanda Lins Brandão Mügge ◽

Viviane Grazielle-Silva ◽

Bruna Mattioly Valente ◽

Wanessa Moreira Goes ◽

...

Keyword(s):

Gene Expression ◽

Trypanosoma Cruzi ◽

Zinc Finger ◽

Rna Binding ◽

Environmental Changes ◽

Zinc Finger Protein ◽

Negative Regulator ◽

Transcriptional Level ◽

Control Of Gene Expression ◽

Genes Encoding

SummaryTrypanosoma cruzi has three biochemically and morphologically distinct developmental stages that are programed to rapidly respond to environmental changes the parasite faces during its life cycle. Unlike other eukaryotes, Trypanosomatid genomes contain protein coding genes that are transcribed into polycistronic pre-mRNAs and control of gene expression relies on mechanisms acting at the post-transcriptional level. Transcriptome analyses comparing epimastigote, trypomastigote and intracellular amastigote stages revealed changes in gene expression that reflect the parasite adaptation to distinct environments. Several genes encoding RNA binding proteins (RBP), known to act as key post-transcriptional regulatory factors, were also differentially expressed. We characterized one T. cruzi RBP (TcZH3H12) that contains a zinc finger domain, and whose transcripts are upregulated in epimastigotes compared to trypomastigotes and amastigotes. TcZC3H12 knockout epimastigotes showed decreased growth rates and increased capacity to differentiate into metacyclic trypomastigotes. Comparative transcriptome analysis revealed a TcZC3H12-dependent expression of epimastigote specific genes encoding amino acid transporters and proteins associated with differentiation (PAD), among others. RNA immunoprecipitation assays showed that transcripts from the PAD family interact with TcZC3H12. Taken together, these findings suggest that TcZC3H12 positively regulates the expression of genes involved in epimastigote proliferation and also acts as a negative regulator of metacyclogenesis.

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

Cancers ◽

10.3390/cancers12061539 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1539 ◽

Cited By ~ 2

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.

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