Herpes Simplex Virus Type 1 Infection Induces Activation and Recruitment of Protein Kinase C to the Nuclear Membrane and Increased Phosphorylation of Lamin B

Park, Richard; Baines, Joel D.

doi:10.1128/jvi.80.1.494-504.2006

Cited by 168 publications

(242 citation statements)

References 36 publications

(56 reference statements)

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“…In this context, p32 appears to be an important factor for establishing the NEC due to its various protein-protein interactions with pUL50, pUL53, pUL97, PKC and LBR (Milbradt et al, 2007;Marschall et al, 2005;Mylonis et al, 2004;Storz et al, 2000;Robles-Flores et al, 2002). Additionally, the recruitment of cellular and viral protein kinases to the nuclear rim is essential for the reorganization of the nuclear lamina (Muranyi et al, 2002;Park & Baines, 2006). In contrast with the observed pUL50-mediated relocalization of PKCa, even in the absence of pUL53, an association of the HSV-1 homologues of pUL50 and pUL53 appears to be required for a similar nuclear rim recruitment of PKC in HSV-1-infected cells (Park & Baines, 2006).…”

Section: Imaging Of Protein Complex Formation At the Nuclear Laminamentioning

confidence: 99%

“…PKC and pUL97. There is accumulating evidence that the involvement of both cellular and viral protein kinases (some of which possess direct lamin-phosphorylating activity) is important for the regulation of nuclear egress of other herpesviruses as well (Klupp et al, 2001;Reynolds et al, 2002;Marschall et al, 2005;Bjerke & Roller, 2006;Park & Baines, 2006;Kato et al, 2006;Leach et al, 2007). It will be crucial to determine the exact phosphorylation target sites on lamins and lamina-associated proteins of these protein kinases for a detailed understanding of the cytomegaloviral nuclear egress.…”

Section: Conclusion: Model Of a Postulated Viral-cellular Multi-protementioning

confidence: 99%

“…Additionally, the recruitment of cellular and viral protein kinases to the nuclear rim is essential for the reorganization of the nuclear lamina (Muranyi et al, 2002;Park & Baines, 2006). In contrast with the observed pUL50-mediated relocalization of PKCa, even in the absence of pUL53, an association of the HSV-1 homologues of pUL50 and pUL53 appears to be required for a similar nuclear rim recruitment of PKC in HSV-1-infected cells (Park & Baines, 2006). Our data suggest that pUL50 is sufficient to induce recruitment of PKC to the nuclear lamina, at least in transfected cells.…”

Section: Imaging Of Protein Complex Formation At the Nuclear Laminamentioning

confidence: 99%

“…protein kinase C (PKC) and cdc2 (Cdk1), are known to phosphorylate the nuclear lamins during prometaphase of the cell cycle, leading to destabilization of the nuclear lamina (Peter et al 1990;Collas et al, 1997). Recruitment of PKC to the nuclear membrane occurs during infection with HCMV, murine cytomegalovirus (MCMV) and herpes simplex virus type-1 (HSV-1) (Muranyi et al, 2002;Park & Baines, 2006;Milbradt et al, 2007). A conserved group of herpesvirus-encoded lamina-associated proteins have been implicated in the recruitment of PKC, the rearrangement of nuclear lamina components and viral nuclear egress (Reynolds et al, 2004;Muranyi et al, 2002;Leach et al, 2007;Morris et al, 2007;Fuchs et al, 2002;Farina et al, 2005;Milbradt et al, 2007; Camozzi et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Cytomegaloviral proteins that associate with the nuclear lamina: components of a postulated nuclear egress complex

Milbradt

Auerochs

Sticht

et al. 2009

Journal of General Virology

147

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The nuclear egress of cytomegaloviral capsids traversing the nuclear envelope is dependent on a locally restricted destabilization of the rigid nuclear lamina. It has been suggested that the multicomponent nuclear egress complex (NEC) that is formed is comprised of both viral and cellular proteins which act to recruit lamin-phosphorylating protein kinases. Recently, we reported that the lamina-associated human cytomegalovirus-encoded proteins pUL50 and pUL53, conserved among herpesviruses, interact with each other and recruit protein kinase C (PKC) to the nuclear envelope in transfected cells. The multiple interactions of the transmembrane protein pUL50 with pUL53, PKC and cellular PKC-binding protein p32, appear crucial to the formation of the NEC. In this study, we mapped individual interaction sequence elements of pUL50 by coimmunoprecipitation analysis of deletion mutants and yeast two-hybrid studies. Amino acids 1-250 were shown to be responsible for interaction with pUL53, 100-280 for PKC and 100-358 for p32. Interestingly, p32 specifically interacted with multiple NEC components, including the kinases PKC and pUL97, thus possibly acting as an adaptor for protein recruitment to the lamin B receptor. Notably, p32 was the only protein that interacted with the lamin B receptor. Immunofluorescence studies visualized the colocalization of NEC components at the nuclear rim in coexpression studies. The data imply that a tight interaction between at least six viral and cellular proteins leads to the formation of a postulated multi-protein complex required for nuclear egress. INTRODUCTIONHuman cytomegalovirus (HCMV), a member of the bherpesvirus subfamily, is a ubiquitous, clinically important human pathogen that causes severe systemic disease in immunosuppressed hosts and prenatally infected children (Mocarski et al., 2007). As is characteristic for most DNA viruses, HCMV replicates its genome in the nucleus of the host cell. Thereafter, preformed viral capsids are packaged with genomic DNA and have to be transported to the cytoplasm for final maturation and viral release. Due to the large size of cytomegaloviral capsids (~130 nm; Chen et al., 1999), these cannot be transported through the nuclear pore complex (~40 nm; Panté & Kann, 2002). The most widely accepted model for nuclear egress of HCMV and other herpesviruses is based on a transient primary envelopment by budding through the inner nuclear membrane (Mettenleiter, 2004(Mettenleiter, , 2006Sanchez & Spector, 2002;Sampaio et al., 2005). However, before herpesvirusencoded capsids gain access to the inner nuclear membrane, the rigid proteinaceous network of the nuclear lamina provides a major obstacle. Thus, the locally restricted destabilization of the nuclear lamina is required during the viral replication process .A basic principle of the reorganization of the nuclear lamina is the recruitment of cellular and/or virus-encoded protein kinases to increase the site-specific phosphorylation of nuclear lamins and lamin-binding proteins (Dechat et al., 2008). Ce...

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Section: Imaging Of Protein Complex Formation At the Nuclear Laminamentioning

confidence: 99%

Section: Conclusion: Model Of a Postulated Viral-cellular Multi-protementioning

confidence: 99%

Section: Imaging Of Protein Complex Formation At the Nuclear Laminamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cytomegaloviral proteins that associate with the nuclear lamina: components of a postulated nuclear egress complex

Milbradt

Auerochs

Sticht

et al. 2009

Journal of General Virology

147

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“…pUL31 and pUL34 bind nuclear lamins A/C and B (15,18,20) and are required for recruitment of cellular protein kinase C (PKC). Phosphorylation of lamins presumably leads to local dissolution of the lamina (12,21). Both proteins are also components of the primary virion but are absent from mature virus particles (8,10,11,22,23).…”

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confidence: 99%

Vesicle formation from the nuclear membrane is induced by coexpression of two conserved herpesvirus proteins

Klupp

Granzow²,

Fuchs³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

164

201

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Although the nuclear envelope is a dynamic structure that disassembles and reforms during mitosis, the formation of membranous vesicles derived from the nuclear envelope has not yet been described in noninfected cells. However, during herpesvirus maturation, intranuclear capsids initiate transit to the cytosol for final maturation by budding at the inner nuclear membrane. Two conserved herpesvirus proteins are required for this primary envelopment, designated in the alphaherpesviruses as pUL31 and pUL34. Here, we show that simultaneous expression of pUL31 and pUL34 of the alphaherpesvirus pseudorabies virus in stably transfected rabbit kidney cells resulted in the formation of vesicles in the perinuclear space that resemble primary envelopes without a nucleocapsid. They contain pUL31 and pUL34 as shown by immunolabeling and are derived from the nuclear envelope. Thus, coexpression of only two conserved herpesvirus proteins without any other viral factor is sufficient to induce the formation of vesicles from the nuclear membrane. This argues for the contribution of cellular factors in this process either recruited from their natural cytoplasmic location or not yet identified as components of the nuclear compartment.nuclear envelope ͉ primary envelopment ͉ pseudorabies virus ͉ herpesvirus egress H erpesvirus particles are complex macromolecular assemblies consisting of Ͼ30 virally encoded proteins, which make up four morphologically distinct structures, core, capsid, tegument, and envelope. Herpesvirus morphogenesis proceeds in two different cellular compartments. While capsid assembly and DNA packaging take place in the nuclei of infected cells, acquisition of the majority of tegument and final envelopment occur in the cytoplasm. To gain access to the cytoplasm the nucleocapsid has to traverse the nuclear lamina and the inner and outer nuclear membranes, because the diameter of the nuclear pores is too small to allow exit of the Ϸ110-nm particle. Although alternative mechanisms for nuclear egress have been proposed, most data support a model that entails primary envelopment by budding of capsids at the inner nuclear membrane resulting in the formation of primary virions in the perinuclear space whose envelope then fuses with the outer nuclear membrane to release the capsid into the cytoplasm (reviewed in ref. 1).The molecular mechanism of this budding, scission, and fusion reaction is unknown. Glycoproteins gB and gH, which are essential for fusion of the viral envelope with the plasma membrane during entry (2) as well as for cell-cell spread, are not required for virion formation indicating that a different molecular mechanism is responsible for fusion during nuclear egress (3). Cellular fusion processes involving the nuclear membranes occur during mitosis. However, the fusion machinery involved is unknown. Soluble N-ethylmaleimide sensitive factor attachment protein receptors ( Two conserved herpesvirus proteins, in the alphaherpesviruses designated as pUL31 and pUL34, are required for nuclear egress of herpesv...

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Nuclear envelope budding: Getting large macromolecular complexes out of the nucleus

Sule,

Nakamura,

Parkhurst

2023

BioEssays

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Transport of macromolecules from the nucleus to the cytoplasm is essential for nearly all cellular and developmental events, and when mis‐regulated, is associated with diseases, tumor formation/growth, and cancer progression. Nuclear Envelope (NE)‐budding is a newly appreciated nuclear export pathway for large macromolecular machineries, including those assembled to allow co‐regulation of functionally related components, that bypasses canonical nuclear export through nuclear pores. In this pathway, large macromolecular complexes are enveloped by the inner nuclear membrane, transverse the perinuclear space, and then exit through the outer nuclear membrane to release its contents into the cytoplasm. NE‐budding is a conserved process and shares many features with nuclear egress mechanisms used by herpesviruses. Despite its biological importance and clinical relevance, little is yet known about the regulatory and structural machineries that allow NE‐budding to occur in any system. Here we summarize what is currently known or proposed for this intriguing nuclear export process.

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Herpes Simplex Virus Type 1 Infection Induces Activation and Recruitment of Protein Kinase C to the Nuclear Membrane and Increased Phosphorylation of Lamin B

Cited by 168 publications

References 36 publications

Cytomegaloviral proteins that associate with the nuclear lamina: components of a postulated nuclear egress complex

Cytomegaloviral proteins that associate with the nuclear lamina: components of a postulated nuclear egress complex

Vesicle formation from the nuclear membrane is induced by coexpression of two conserved herpesvirus proteins

Nuclear envelope budding: Getting large macromolecular complexes out of the nucleus

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