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Viral hijacking of the TENT4-ZCCHC14 complex protects viral RNAs via mixed tailing

Cited 19 time in Web of Science Cited 20 time in Scopus
Issue Date
2020-06
Citation
Nature Structural and Molecular Biology, Vol.27 No.6, pp.581-588
Abstract
Mixed tailing of hepatitis B virus and human cytomegalovirus transcripts via recruitment of the TENT4-ZCCHC14 complex by a common RNA element protects viral RNAs from degradation. TENT4 enzymes generate 'mixed tails' of diverse nucleotides at 3 ' ends of RNAs via nontemplated nucleotide addition to protect messenger RNAs from deadenylation. Here we discover extensive mixed tailing in transcripts of hepatitis B virus (HBV) and human cytomegalovirus (HCMV), generated via a similar mechanism exploiting the TENT4-ZCCHC14 complex. TAIL-seq on HBV and HCMV RNAs revealed that TENT4A and TENT4B are responsible for mixed tailing and protection of viral poly(A) tails. We find that the HBV post-transcriptional regulatory element (PRE), specifically the CNGGN-type pentaloop, is critical for TENT4-dependent regulation. HCMV uses a similar pentaloop, an interesting example of convergent evolution. This pentaloop is recognized by the sterile alpha motif domain-containing ZCCHC14 protein, which in turn recruits TENT4. Overall, our study reveals the mechanism of action of PRE, which has been widely used to enhance gene expression, and identifies the TENT4-ZCCHC14 complex as a potential target for antiviral therapeutics.
ISSN
1545-9993
URI
https://hdl.handle.net/10371/178038
DOI
https://doi.org/10.1038/s41594-020-0427-3
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