Document Detail


The "Bridge" in the Epstein-Barr virus alkaline exonuclease protein BGLF5 contributes to shutoff activity during productive infection.
MedLine Citation:
PMID:  22696660     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Replication of the human herpesvirus Epstein-Barr virus drastically impairs cellular protein synthesis. This shutoff phenotype results from mRNA degradation upon expression of the early lytic-phase protein BGLF5. Interestingly, BGLF5 is the viral DNase, or alkaline exonuclease, homologues of which are present throughout the herpesvirus family. During productive infection, this DNase is essential for processing and packaging of the viral genome. In contrast to this widely conserved DNase activity, shutoff is only mediated by the alkaline exonucleases of the subfamily of gammaherpesviruses. Here, we show that BGLF5 can degrade mRNAs of both cellular and viral origin, irrespective of polyadenylation. Furthermore, shutoff by BGLF5 induces nuclear relocalization of the cytosolic poly(A) binding protein. Guided by the recently resolved BGLF5 structure, mutants were generated and analyzed for functional consequences on DNase and shutoff activities. On the one hand, a point mutation destroying DNase activity also blocks RNase function, implying that both activities share a catalytic site. On the other hand, other mutations are more selective, having a more pronounced effect on either DNA degradation or shutoff. The latter results are indicative of an oligonucleotide-binding site that is partially shared by DNA and RNA. For this, the flexible "bridge" that crosses the active-site canyon of BGLF5 appears to contribute to the interaction with RNA substrates. These findings extend our understanding of the molecular basis for the shutoff function of BGLF5 that is conserved in gammaherpesviruses but not in alpha- and betaherpesviruses.
Authors:
Daniëlle Horst; Wim P Burmeister; Ingrid G J Boer; Daphne van Leeuwen; Marlyse Buisson; Alexander E Gorbalenya; Emmanuel J H J Wiertz; Maaike E Ressing
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-06-13
Journal Detail:
Title:  Journal of virology     Volume:  86     ISSN:  1098-5514     ISO Abbreviation:  J. Virol.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-08-10     Completed Date:  2012-11-05     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  0113724     Medline TA:  J Virol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  9175-87     Citation Subset:  IM    
Affiliation:
Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, Netherlands.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Motifs
Amino Acid Sequence
Cell Line
Deoxyribonucleases / chemistry*,  genetics,  metabolism*
Epstein-Barr Virus Infections / genetics*,  metabolism,  virology*
Herpesvirus 4, Human / chemistry,  enzymology*,  genetics,  physiology*
Humans
Molecular Sequence Data
Protein Biosynthesis
RNA Stability
Sequence Alignment
Viral Proteins / chemistry*,  genetics,  metabolism*
Virus Replication
Chemical
Reg. No./Substance:
0/Viral Proteins; EC 3.1.-/Deoxyribonucleases; EC 3.1.11.-/deoxyribonuclease, Epstein-Barr virus
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