A deneddylase encoded by Epstein-Barr virus promotes viral DNA replication by regulating the activity of cullin-RING ligases.
The large tegument proteins of herpesviruses encode conserved cysteine proteases of unknown function. Here we show that BPLF1, the Epstein-Barr-virus-encoded member of this protease family, is a deneddylase that regulates virus production by modulating the activity of cullin-RING ligases (CRLs). BPLF1 hydrolyses NEDD8 conjugates in vitro, acts as a deneddylase in vivo, binds to cullins and stabilizes CRL substrates. Expression of BPLF1 alone or in the context of the productive virus cycle induces accumulation of the licensing factor CDT1 and deregulates S-phase DNA synthesis. Inhibition of BPLF1 during the productive virus cycle prevents cellular DNA re-replication and inhibits virus replication. Viral DNA synthesis is restored by overexpression of CDT1. Homologues encoded by other herpesviruses share the deneddylase activity. Thus, these enzymes are likely to have a key function in the virus life cycle by inducing a replication-permissive S-phase-like cellular environment.
Gastaldello
Stefano
S
Department of Cell and Molecular Biology, Karolinska Institutet, Box 285, S-17177 Stockholm, Sweden.
Hildebrand
Sebastian
S
Faridani
Omid
O
Callegari
Simone
S
Palmkvist
Mia
M
Di Guglielmo
Claudia
C
Masucci
Maria G
MG
D018797:Cell Cycle Proteins / Q000378:metabolism; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication; D004279:DNA, Viral / Q000096:biosynthesis*; D017930:Genes, Reporter; D006367:HeLa Cells; D004854:Herpesvirus 4, Human / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity; D006801:Humans; D006868:Hydrolysis; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016196:S Phase; D013997:Time Factors; D014162:Transfection; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism*; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication
C495488:BPLF1 protein, Epstein-Barr virus; D018797:Cell Cycle Proteins; D044842:Cullin Proteins; D004279:DNA, Viral; D011993:Recombinant Fusion Proteins; D014452:Ubiquitins; D054334:Viral Regulatory and Accessory Proteins