Targeting of the gene product encoded by ORF UL56 of human cytomegalovirus into viral replication centers

Giesen, Kyra; Radsak, K.; Bogner, Elke

doi:10.1016/s0014-5793(00)01407-1

Cited by 26 publications

(20 citation statements)

References 23 publications

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“…5A, in cells infected with HD-UL51-NHA, pUL51 was enriched in the same nuclear compartments as pUL56 and pUL89. It has been shown that pUL56 localizes to viral DNA replication compartments (58) and, thus, we concluded that pUL51 is present in these subnuclear structures. In order to explore whether pUL51 does interact with pUL56 or pUL89, we applied affinity purification after infecting HFF with HD-UL51-SF, expressing pUL51 fused to the Strep-Flag tag.…”

Section: Hcmv Ul51 Mutantmentioning

confidence: 55%

The Human Cytomegalovirus UL51 Protein Is Essential for Viral Genome Cleavage-Packaging and Interacts with the Terminase Subunits pUL56 and pUL89

Borst

Kleine-Albers

Gabaev

et al. 2013

J Virol

107

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dCleavage of human cytomegalovirus (HCMV) genomes as well as their packaging into capsids is an enzymatic process mediated by viral proteins and therefore a promising target for antiviral therapy. The HCMV proteins pUL56 and pUL89 form the terminase and play a central role in cleavage-packaging, but several additional viral proteins, including pUL51, had been suggested to contribute to this process, although they remain largely uncharacterized. To study the function of pUL51 in infected cells, we constructed HCMV mutants encoding epitope-tagged versions of pUL51 and used a conditionally replicating virus (HCMV-UL51-ddFKBP), in which pUL51 levels could be regulated by a synthetic ligand. In cells infected with HCMV-UL51-ddFKBP, viral DNA replication was not affected when pUL51 was knocked down. However, no unit-length genomes and no DNA-filled C capsids were found, indicating that cleavage of concatemeric HCMV DNA and genome packaging into capsids did not occur in the absence of pUL51. pUL51 was expressed mainly with late kinetics and was targeted to nuclear replication compartments, where it colocalized with pUL56 and pUL89. Upon pUL51 knockdown, pUL56 and pUL89 were no longer detectable in replication compartments, suggesting that pUL51 is needed for their correct subnuclear localization. Moreover, pUL51 was found in a complex with the terminase subunits pUL56 and pUL89. Our data provide evidence that pUL51 is crucial for HCMV genome cleavage-packaging and may represent a third component of the viral terminase complex. Interference with the interactions between the terminase subunits by antiviral drugs could be a strategy to disrupt the HCMV replication cycle.

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Section: Hcmv Ul51 Mutantmentioning

confidence: 55%

The Human Cytomegalovirus UL51 Protein Is Essential for Viral Genome Cleavage-Packaging and Interacts with the Terminase Subunits pUL56 and pUL89

Borst

Kleine-Albers

Gabaev

et al. 2013

J Virol

107

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“…Direct interaction of the pUL56 NLS with importin a implied that nuclear translocation is mediated by the importin-dependent pathway. Furthermore, it was found that pUL56 is predominantly localised in viral replication centers at late times of infection ( Figure 3) [43]. In these replication centers pUL56 co-localises alongside pUL112-113 as well as pUL44, proteins known to be involved in DNA replication.…”

Section: Introductionmentioning

confidence: 95%

Human cytomegalovirus terminase as a target for antiviral chemotherapy

Bogner¹

2002

Reviews in Medical Virology

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Herpesviral DNA packaging is a complex process involving binding and cleavage of DNA containing the specific DNA-packaging motifs, pac1 and pac2, and packaging of the resulting unit-length genomes into preformed procapsids. This process is believed to be mediated by two packaging proteins, the terminase subunits. In the case of human cytomegalovirus the terminase consists of the proteins pUL56 and pUL89. While pUL56 (i) mediates the specific binding to pac sequences on the concatamers, (ii) provides energy for the translocation of the DNA to the procapsids and (iii) associates itself with the capsid for enabling the entry of the DNA into the procapsid, pUL89 is mainly required to effect DNA cleavage. Based on the limited efficacy of the current drugs ganciclovir, cidofovir and foscarnet, new antiviral therapeutics appear to be in demand. Inhibitors targeting pUL56 and/or pUL89 may offer an attractive alternative since mammalian cell DNA replication does not involve cleavage of concatameric DNA. Drugs targeted to terminase-like proteins should therefore be safe and highly selective.

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“…The viral protein responsible for DNA binding during the packaging process, UL56, is found within replication compartments. UL56 localization to replication compartments is dependent on viral DNA synthesis, and UL56 may interact with UL44 within replication compartments (Giesen et al, 2000). Furthermore, it has been speculated that packaging of viral DNA into capsids is responsible for the movement of newly synthesized viral DNA from the periphery of replication compartments to the interior of replication compartments (Strang et al, 2012b).…”

Section: Structures Associated With Hcmv Replication: Nucleoli Cajalmentioning

confidence: 99%

Viral and cellular subnuclear structures in human cytomegalovirus-infected cells

Strang

2015

Journal of General Virology

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In human cytomegalovirus (HCMV)-infected cells, a dramatic remodelling of the nuclear architecture is linked to the creation, utilization and manipulation of subnuclear structures. This review outlines the involvement of several viral and cellular subnuclear structures in areas of HCMV replication and virus-host interaction that include viral transcription, viral DNA synthesis and the production of DNA-filled viral capsids. The structures discussed include those that promote or impede HCMV replication (such as viral replication compartments and promyelocytic leukaemia nuclear bodies, respectively) and those whose role in the infected cell is unclear (for example, nucleoli and nuclear speckles). Viral and cellular proteins associated with subnuclear structures are also discussed. The data reviewed here highlight advances in our understanding of HCMV biology and emphasize the complexity of HCMV replication and virus-host interactions in the nucleus. IntroductionThe betaherpesvirus human cytomegalovirus (HCMV) is a widespread opportunistic pathogen that severely affects immunocompromised and immunodeficient populations (Mocarski et al., 2007). Like all herpesviruses, HCMV undergoes either productive or latent infection. During productive infection, infectious virus is produced, while in latent infection the virus becomes largely transcriptionally quiescent (Mocarski et al., 2007). Like other herpesviruses, many events that are critical for productive HCMV replication take place within the nucleus. These include essential steps in viral replication, such as: the transcriptional cascade of immediate-early (IE), early and late viral RNA transcripts, synthesis of viral DNA and the production of DNA-containing capsids (Mocarski et al., 2007). Compared with the prototype human herpesvirus, the alphaherpesvirus herpes simplex virus (HSV), certain features of productive HCMV infection are not well characterized. However, it is clear that several subnuclear structures are involved in HCMV genome replication and virus-host interactions. Uncovering the roles of these structures has led to significant advances in our understanding of HCMV biology. This review summarizes the involvement of several viral and cellular subnuclear structures in productive HCMV infection. The participation of each structure in HCMV replication and virus-host interactions is described from entry of the viral genome into the nucleus to the egress of viral capsids through the nuclear membrane. The data discussed highlight recent advances in our understanding of subnuclear structure function, introduce viral and cellular factors associated with subnuclear structures and indicate what questions have yet to be answered.Entry of the HCMV genome into the nucleus: the nuclear pore complex, nuclear speckles, promyelocytic leukaemia protein nuclear bodies and pp150 bodies HCMV genome entry into the nucleus is poorly defined but may be similar to movement of the HSV DNA genome through the nuclear pore complex (NPC) (Kobiler et al., 2012) (Fig. 1a). HCMV capsid ...

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Targeting of the gene product encoded by ORF UL56 of human cytomegalovirus into viral replication centers

Cited by 26 publications

References 23 publications

The Human Cytomegalovirus UL51 Protein Is Essential for Viral Genome Cleavage-Packaging and Interacts with the Terminase Subunits pUL56 and pUL89

The Human Cytomegalovirus UL51 Protein Is Essential for Viral Genome Cleavage-Packaging and Interacts with the Terminase Subunits pUL56 and pUL89

Human cytomegalovirus terminase as a target for antiviral chemotherapy

Viral and cellular subnuclear structures in human cytomegalovirus-infected cells

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