Abstract
The adenovirus type 5 (Ad5) E1B 55 kDa and E4 Orf6 proteins assemble a Cullin 5-E3 ubiquitin (Ub) ligase that targets, among other cellular proteins, p53 and the Mre11-Rad50-Nbs1 (MRN) complex for degradation. The latter is also inhibited by the E4 Orf3 protein, which promotes the recruitment of Mre11 into specific nuclear sites to promote viral DNA replication. The activities associated with the E1B 55 kDa and E4 Orf6 viral proteins depend mostly on the assembly of this E3-Ub ligase. However, E1B 55 kDa can also function as an E3-SUMO ligase, suggesting not only that regulation of cellular proteins by these viral early proteins may depend on polyubiquitination and proteasomal degradation but also that SUMOylation of target proteins may play a key role in their activities. Since Mre11 is a target of both the E1B/E4 Orf6 complex and E4 Orf3, we decided to determine whether Mre11 displayed similar properties to those of other cellular targets, in Ad5-infected cells. We have found that during Ad5-infection, Mre11 is modified by SUMO-1 and SUMO-2/3 conjugation. Unexpectedly, SUMOylation of Mre11 is not exclusively dependent on E1B 55 kDa, E4 Orf6, or E4 Orf3, rather it seems to be influenced by a molecular interplay that involves each of these viral early proteins.
Highlights
The adenoviral E1B 55 kDa, E4 Orf6, and E4 Orf3 early proteins are necessary to complete an efficient viral replication cycle
During adenovirus type 5 (Ad5)-infection of cultured human cells the DNA damage response (DDR) is initially inhibited by the E4 Orf3 protein, which disrupts PML nuclear bodies (PML NBs) and induces the intracellular redistribution of Mre11 to these sites, prior to its targeted polyubiquitination and proteasomal degradation directed by E1B 55 kDa and E4 Orf6 [8, 14, 22,23,24, 71]
In order to investigate if Mre11 is subject to similar processes, we decided to analyze whether degradation of Mre11 is induced in Ad5-infected human foreskin fibroblasts (HFF)
Summary
The adenoviral E1B 55 kDa, E4 Orf, and E4 Orf early proteins are necessary to complete an efficient viral replication cycle. Inhibition of DSBR is necessary to avoid concatemerization of the viral genome and to promote efficient viral DNA replication [20,21,22,23,24]. These activities depend on the E4 Orf protein, another early gene product that interacts with E1B 55 kDa as well as the isoform II of the promyelocytic leukemia protein (PML). Thereby E4 Orf initiates the reorganization of PML nuclear bodies (PML NBs) and formation of nuclear sites where the viral genome is replicated and expressed [8, 22, 23, 25,26,27,28,29]
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