Role and Fate of PML-Associated Nuclear Bodies in Reponse to HCMV Infection

다국어 초록 (Multilingual Abstract)

Human cytomegalovirus(HCMV), a member of the betaherpesvirus subfamily, is a ubiquitous pathogen, which can cause congenital disease and also produces serious complications in immunocompromised individuals. In HCMV-infected cells, the immediate-early(IE) proteins govern the downstream viral gene expression and have regulatory roles in modulating host cell functions. Recently, the HCMV IE1 protein, which is essential for viral growth at low multiplicity of infection, was found to be modified by small ubiquitin-like modifiers(SUMO). The lysine residue at 450 of IE1 was mapped as a SUMO attachment site. A recombinant HCMV encoding sumoylation-deficient mutant IE1 was generated from the HCMV-bacterial artificial chromosome(BAC) clone and displayed a slightly reduced viral growth, suggesting that IE1 sumoylation may promote viral replication. IE1 has also been shown to target to and disrupt the subnuclear structures known as PML oncogenic domains(PODs) or nuclear bodies. Sumoylation of PML is required for the formation of these matrix-associated structures. Interestingly, IE1 was found to disrupt PODs by inducing desumoylation of PML. This activity required PML binding, but not IE1 sumoylation, and correlated with the functions of IE1 in transcriptional regulation. Genetic analysis with HCMV-BAC clones revealed that the IE1-induced POD disruption is necessary for efficient viral replication. Further analysis revealed that IE1 interferes with the PML-mediated transcriptional repression, and that the formation of IE1-PML-histone deacetylase(HDAC) complex blocks the type-Ⅰ interferon(IFN) signaling by inhibiting the activation of IFN-stimulated response elements(ISREs). Collectively, these data suggest that the IE1-induced POD disruption(and the IE1-PML interaction) plays important roles in counteracting the POD(or PML)-mediated intrinsic anti-viral responses and in generating nuclear environment for efficient viral replication.