Viral and host control of cytomegalovirus maturation

Tandon, Ritesh; Mocarski, Edward S.

doi:10.1016/j.tim.2012.04.008

Cited by 109 publications

(169 citation statements)

References 96 publications

(174 reference statements)

Supporting

Mentioning

161

Contrasting

Unclassified

Order By: Relevance

“…7 During the formation of the AC, extensive cytoplasmic remodeling occurs, resulting in dramatic reorientation of the secretory machinery, including the early endosomes. 6,7,10,14 Although RhoB has been reported to localize to early endosomes, 20 it is not fully spatially associated with the early endosome protein Rab5 65,66 in HCMV-infected cells (Fig. 1G lower panel).…”

Section: Discussionmentioning

confidence: 98%

“…The endosomal sorting complex required for transport (ESCRT) machinery and multivesicular bodies (MVB) play a role in virion maturation. [6][7][8][9][10][11][12][13][14] RhoB belongs to the Rho GTPase family of proteins that comprises 6 subfamilies. 15 The RhoA subfamily consists of RhoA, RhoB and RhoC, which exhibit approximately 85% amino acid sequence identity.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

RhoB is a component of the human cytomegalovirus assembly complex and is required for efficient viral production

et al. 2015

View full text Add to dashboard Cite

Human Cytomegalovirus (HCMV), an ubiquitous b-herpesvirus, is a significant pathogen that causes medically severe diseases in immunocompromised individuals and in congenitally infected neonates. RhoB belongs to the family of Rho GTPases, which regulates diverse cellular processes. Rho proteins are implicated in the entry and egress from the host cell of mainly a-and g-herpesviruses, whereas b-herpesviruses are the least studied in this regard. Here, we studied the role of RhoB GTPase during HCMV lytic infection. Microscopy analysis, both in fixed and live infected cells showed that RhoB was translocated to the assembly complex/compartment (AC) of HCMV, a cytoplasmic zone in infected cells where many viral structural proteins are known to accumulate and assembly of new virions takes place. Furthermore, RhoB was localized at the AC even when the expression of the late HCMV AC proteins was inhibited. At the very late stages of infection, cellular projections were formed containing RhoB and HCMV virions, potentially contributing to the successful viral spread. Interestingly, the knockdown of RhoB in HCMV-infected cells resulted in a significant reduction of the virus titer and could also affect the accumulation of AC viral proteins at this subcellular compartment. RhoB knockdown also affected actin fibers' structure. Actin reorganization was observed at late stages of infection originating from the viral AC and surrounding the cellular projections, implying a potential interplay between RhoB and actin during HCMV assembly and egress. In conclusion, our results demonstrate for the first time that RhoB is a constituent of the viral AC and is required for HCMV productive infection.

show abstract

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

RhoB is a component of the human cytomegalovirus assembly complex and is required for efficient viral production

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Successful genome packaging generates DNA-filled C capsids. The two other nuclear capsid forms are empty shells, with B capsids probably arising from spontaneous angularization of procapsids and A capsids originating from abortive packaging events without retention of the genomes within the capsids (1,3,5,6). B capsids were recently discussed to be intermediate capsid forms during the genome packaging process rather than dead end products (7).…”

mentioning

confidence: 99%

The Essential Human Cytomegalovirus Proteins pUL77 and pUL93 Are Structural Components Necessary for Viral Genome Encapsidation

Borst

Bauerfeind

Binz

et al. 2016

J Virol

View full text Add to dashboard Cite

Several essential viral proteins are proposed to participate in genome encapsidation of human cytomegalovirus (HCMV), among them pUL77 and pUL93, which remain largely uncharacterized. To gain insight into their properties, we generated an HCMV mutant expressing a pUL77-monomeric enhanced green fluorescent protein (mGFP) fusion protein and a pUL93-specific antibody. Immunoblotting demonstrated that both proteins are incorporated into capsids and virions. Conversely to data suggesting internal translation initiation sites within the UL93 open reading frame (ORF), we provide evidence that pUL93 synthesis commences at the first start codon. In infected cells, pUL77-mGFP was found in nuclear replication compartments and dot-like structures, colocalizing with capsid proteins. Immunogold labeling of nuclear capsids revealed that pUL77 is present on A, B, and C capsids. Pulldown of pUL77-mGFP revealed copurification of pUL93, indicating interaction between these proteins, which still occurred when capsid formation was prevented. Correct subnuclear distribution of pUL77-mGFP required pUL93 as well as the major capsid protein (and thus probably the presence of capsids), but not the tegument protein pp150 or the encapsidation protein pUL52, demonstrating that pUL77 nuclear targeting occurs independently of the formation of DNA-filled capsids. When pUL77 or pUL93 was missing, generation of unit-length genomes was not observed, and only empty B capsids were produced. Taken together, these results show that pUL77 and pUL93 are capsid constituents needed for HCMV genome encapsidation. Therefore, the task of pUL77 seems to differ from that of its alphaherpesvirus orthologue pUL25, which exerts its function subsequent to genome cleavage-packaging. IMPORTANCEThe essential HCMV proteins pUL77 and pUL93 were suggested to be involved in viral genome cleavage-packaging but are poorly characterized both biochemically and functionally. By producing a monoclonal antibody against pUL93 and generating an HCMV mutant in which pUL77 is fused to a fluorescent protein, we show that pUL77 and pUL93 are capsid constituents, with pUL77 being similarly abundant on all capsid types. Each protein is required for genome encapsidation, as the absence of either pUL77 or pUL93 results in a genome packaging defect with the formation of empty capsids only. This distinguishes pUL77 from its alphaherpesvirus orthologue pUL25, which is enriched on DNA-filled capsids and exerts its function after the viral DNA is packaged. Our data for the first time describe an HCMV mutant with a fluorescent capsid and provide insight into the roles of pUL77 and pUL93, thus contributing to a better understanding of the HCMV encapsidation network.T he life cycle of human cytomegalovirus (HCMV), the prototype member of the betaherpesviruses, comprises a nuclear phase that includes transcription of viral genes, replication of the double-stranded DNA genome, assembly of procapsids, packaging of the viral DNA into the preformed capsids, and maturation of the DNA-filled c...

show abstract

“…In Focus putative target for novel antiviral strategies 16,[38][39][40][41] . During the nuclear phase of HCMV replication, viral capsids are packaged and exported to the cytoplasm by transition through the nuclear envelope (nuclear egress) for further virion maturation.…”

Section: Inhibitors Of Viral Nuclear Egressmentioning

confidence: 99%

Therapeutics to prevent congenital cytomegalovirus during pregnancy: what is available now and in the future?

2015

View full text Add to dashboard Cite

Human cytomegalovirus (CMV) is the leading non-genetic cause of fetal malformation in developed countries. Congenital CMV infection can cause serious clinical sequelae, and in severe cases result in fetal or neonatal death. Despite the clinical and social importance of congenital CMV there is currently no standardised management strategy to prevent or treat maternal/fetal CMV infection during pregnancy and no evidence-based therapeutic for prenatally diagnosed CMV infection or disease. For pregnant women with a primary CMV infection during pregnancy, standard medical practise remains to offer no treatment at all or the option to terminate pregnancy. If intervention is requested, pregnant women may be offered a narrow range of medical therapies with limited evidence for efficacy and some with high risks of toxicity. However, there are several experimental and novel anti-CMV therapeutics currently being investigated that may provide a safe and effective therapeutic for use during pregnancy to prevent both fetal infection and reduce the risk of congenital CMV disease developing in the fetus once infected in utero.

show abstract

Viral and host control of cytomegalovirus maturation

Cited by 109 publications

References 96 publications

RhoB is a component of the human cytomegalovirus assembly complex and is required for efficient viral production

RhoB is a component of the human cytomegalovirus assembly complex and is required for efficient viral production

The Essential Human Cytomegalovirus Proteins pUL77 and pUL93 Are Structural Components Necessary for Viral Genome Encapsidation

Therapeutics to prevent congenital cytomegalovirus during pregnancy: what is available now and in the future?

Contact Info

Product

Resources

About