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RNA helicases are hubs that orchestrate exosome-dependent 3'-5' decay.

ABSTRACT: The RNA exosome is a conserved complex of proteins that mediates 3'-5' RNA processing and decay. Its functions range from processing of non-coding RNAs such as ribosomal RNAs and decay of aberrant transcripts in the nucleus to cytoplasmic mRNA turnover and quality control. Ski2-like RNA helicases translocate substrates to exosome-associated ribonucleases and interact with the RNA exosome either directly or as part of multi-subunit helicase-containing complexes that identify and target RNA substrates for decay. Recent structures of these helicases with their RNA-binding partners or the RNA exosome have advanced our understanding of a system of modular and mutually exclusive contacts between the exosome and exosome-associated helicase complexes that shape the transcriptome by orchestrating exosome-dependent 3'-5' decay.

SUBMITTER: Weick EM

PROVIDER: S-EPMC8087718 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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RNA helicases are hubs that orchestrate exosome-dependent 3'-5' decay.

Weick Eva-Maria EM Lima Christopher D CD

Current opinion in structural biology 20201102

The RNA exosome is a conserved complex of proteins that mediates 3'-5' RNA processing and decay. Its functions range from processing of non-coding RNAs such as ribosomal RNAs and decay of aberrant transcripts in the nucleus to cytoplasmic mRNA turnover and quality control. Ski2-like RNA helicases translocate substrates to exosome-associated ribonucleases and interact with the RNA exosome either directly or as part of multi-subunit helicase-containing complexes that identify and target RNA substr ...[more]

PMID: 33147539

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Project description: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 by 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 bind directly 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.

Dataset Information

RNA helicases are hubs that orchestrate exosome-dependent 3'-5' decay.

Publications

RNA helicases are hubs that orchestrate exosome-dependent 3'-5' decay.

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