Epstein–Barr virus glycoprotein gM can interact with the cellular protein p32 and knockdown of p32 impairs virus

Changotra, Harish; Turk, Susan M.; Artigues, Antonio; Thakur, Nagendra N.; Gore, Mindy; Muggeridge, Martin I.; Hutt-Fletcher, Lindsey

doi:10.1016/j.virol.2015.12.019

Cited by 11 publications

(11 citation statements)

References 46 publications

(53 reference statements)

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“…As an important feature, the NEC-associated HCMV protein kinase pUL97 interacts with p32/gC1qR, which bridges pUL97 to the pUL50-pUL53 core NEC [54,58]. A similar bridging function of p32/gC1qR has been suggested for the NECs of other α-, βand γ-herpesviruses [49,55,70,71]. In addition to HCMV pUL97, cellular protein kinases were found to be NEC-associated, in particular, PKC and CDK1 [9].…”

Section: Specific Functional Properties Of Necs and Egress Processes mentioning

confidence: 70%

Nuclear Egress Complexes of HCMV and Other Herpesviruses: Solving the Puzzle of Sequence Coevolution, Conserved Structures and Subfamily-Spanning Binding Properties

Marschall

Häge

Conrad

et al. 2020

Viruses

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Herpesviruses uniquely express two essential nuclear egress-regulating proteins forming a heterodimeric nuclear egress complex (core NEC). These core NECs serve as hexameric lattice-structured platforms for capsid docking and recruit viral and cellular NEC-associated factors that jointly exert nuclear lamina as well as membrane-rearranging functions (multicomponent NEC). The regulation of nuclear egress has been profoundly analyzed for murine and human cytomegaloviruses (CMVs) on a mechanistic basis, followed by the description of core NEC crystal structures, first for HCMV, then HSV-1, PRV and EBV. Interestingly, the highly conserved structural domains of these proteins stand in contrast to a very limited sequence conservation of the key amino acids within core NEC-binding interfaces. Even more surprising, although a high functional consistency was found when regarding the basic role of NECs in nuclear egress, a clear specification was identified regarding the limited, subfamily-spanning binding properties of core NEC pairs and NEC multicomponent proteins. This review summarizes the evolving picture of the relationship between sequence coevolution, structural conservation and properties of NEC interaction, comparing HCMV to α-, β- and γ-herpesviruses. Since NECs represent substantially important elements of herpesviral replication that are considered as drug-accessible targets, their putative translational use for antiviral strategies is discussed.

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Section: Specific Functional Properties Of Necs and Egress Processes mentioning

confidence: 70%

Nuclear Egress Complexes of HCMV and Other Herpesviruses: Solving the Puzzle of Sequence Coevolution, Conserved Structures and Subfamily-Spanning Binding Properties

Marschall

Häge

Conrad

et al. 2020

Viruses

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“…In the case of mass spectrometry-based proteomics analyses performed on HCMV and MCMV, both identical and nonidentical components of their multicomponent NECs have been identified [32,35]. One interesting and consistent finding was the presence of the cellular multi-ligand binding protein p32/gC1qR in α-, βand γ-herpesviral NECs [33,35,40,41]. Our data provided additional evidence that p32/gC1qR is able to interact with HCMV-and MCMV-specific core NEC proteins ( Figure 5 and Figure S1).…”

Section: Discussionmentioning

confidence: 88%

Patterns of Autologous and Nonautologous Interactions between Core Nuclear Egress Complex (NEC) Proteins of α-, β- and γ-Herpesviruses

Häge

Sonntag

Borst

et al. 2020

Viruses

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Nuclear egress is a regulated process shared by α-, β- and γ-herpesviruses. The core nuclear egress complex (NEC) is composed of the membrane-anchored protein homologs of human cytomegalovirus (HCMV) pUL50, murine cytomegalovirus (MCMV) pM50, Epstein–Barr virus (EBV) BFRF1 or varicella zoster virus (VZV) Orf24, which interact with the autologous NEC partners pUL53, pM53, BFLF2 or Orf27, respectively. Their recruitment of additional proteins leads to the assembly of a multicomponent NEC, coordinately regulating viral nucleocytoplasmic capsid egress. Here, the functionality of VZV, HCMV, MCMV and EBV core NECs was investigated by coimmunoprecipitation and confocal imaging analyses. Furthermore, a recombinant MCMV, harboring a replacement of ORF M50 by UL50, was analyzed both in vitro and in vivo. In essence, core NEC interactions were strictly limited to autologous NEC pairs and only included one measurable nonautologous interaction between the homologs of HCMV and MCMV. A comparative analysis of MCMV-WT versus MCMV-UL50-infected murine fibroblasts revealed almost identical phenotypes on the levels of protein and genomic replication kinetics. In infected BALB/c mice, virus spread to lung and other organs was found comparable between these viruses, thus stating functional complementarity. In conclusion, our study underlines that herpesviral core NEC proteins are functionally conserved regarding complementarity of core NEC interactions, which were found either virus-specific or restricted within subfamilies.

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“…p32, as a multiligand-binding, multicompartmental, and multifunctional protein, has been reported to mediate viral nuclear egress through binding to viral proteins (26,33,35). Although previous studies have indicated that p32 can facilitate HSV-1 nuclear egress through interaction with HSV-1 ICP34.5 and UL47 to regulate the rearrangement of the nuclear lamina (25,26), the exact roles of p32 in phosphorylation and rearrangement of lamin A/C remain undefined.…”

Section: Discussionmentioning

confidence: 99%

“…p32 has been reported to be involved in the replication process of various viruses by binding to some specific viral proteins, such as herpes simplex virus 1 (HSV-1) UL47 and ICP34.5 (25,26), human immunodeficiency virus Rev and Tat (27,28), adenovirus core protein (29), hepatitis C virus core protein (30), Epstein-Barr virus (EBV) EBNA-1 (31), and human cytomegalovirus (HCMV) UL97, UL50, and UL53 proteins (32,33). p32 is required for the phosphorylation and redistribution of nuclear lamina during the nuclear egress of HSV-1 via interaction with viral ICP34.5 (26) and has also been implicated in the nuclear egress of HCMV and EBV (33)(34)(35). Interestingly, p32 itself is not a kinase, and the only viral protein with kinase activity that has been shown to be associated with intracellular p32 is human CMV pUL97, which phosphorylates nuclear lamin at the inner nuclear membrane during the process of CMV infection (33).…”

mentioning

confidence: 99%

Cellular p32 Is a Critical Regulator of Porcine Circovirus Type 2 Nuclear Egress

Wang

Niu

et al. 2019

J Virol

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Circoviruses are the smallest DNA viruses known to infect mammalian and avian species. Although circoviruses are known to be associated with a range of clinical diseases, the details of circovirus DNA release still remain unknown. Here, we identified p32 as a key regulator for porcine circoviral nuclear egress. Upon porcine circovirus type 2 (PCV2) infection, p32 was recruited into the nucleus by the viral capsid (Cap) protein; simultaneously, protein kinase C isoform δ (PKC-δ) was phosphorylated at threonine 505 by phospholipase C (PLC)-mediated signaling at the early stage of infection, which was further amplified by Jun N-terminal protein kinase (JNK) and extracellular signal-regulated kinase (ERK) signaling at the late infection phase. p32 functioned as an adaptor to recruit phosphorylated PKC-δ and Cap to the nuclear membrane to phosphorylate lamin A/C, resulting in a rearrangement of nuclear lamina and thus facilitating viral nuclear egress. Consistent with these findings, knockout (KO) of p32 in PCV2-infected cells markedly reduced the phosphorylation of PKC-δ and impeded the recruitment of p-PKC-δ and Cap to the nuclear membrane, hence abolishing the phosphorylation of lamin A/C and the rearrangement of nuclear lamina. As a result, p32 depletion profoundly impaired the production of cell-free viruses during PCV2 infection. We further identified the N-terminal 24RRR26 of Cap to be crucial for binding to p32, and mutation of these three arginine residues significantly weakened the replication and pathogenesis of PCV2 in vivo. In summary, our findings highlight a critical role of p32 in the activation and recruitment of PKC-δ to phosphorylate lamin A/C and facilitate porcine circoviral nuclear egress, and they certainly help understanding of the mechanism of PCV2 replication. IMPORTANCE Circovirus infections are highly prevalent in mammalian and avian species. Circoviral capsid protein is the only structural protein of the virion that plays an essential role in viral assembly. However, the machinery of circovirus nuclear egress is currently unknown. In this work, we identified p32 as a key regulator of porcine circovirus type 2 (PCV2) nuclear egress that forms a complex with the viral capsid (Cap) protein to enhance protein kinase C isoform δ (PKC-δ) activity; this resulted in a recruitment of phosphorylated PKC-δ to the nuclear membrane, which further phosphorylates lamin A/C to promote the rearrangement of nuclear lamina and facilitate viral nuclear egress. Notably, we found that the N-terminal 24RRR26 of Cap, a highly conserved motif among circovirus species, was required for interacting with p32, and that mutation of this motif markedly impeded PCV2 nuclear egress. These data indicate that p32 is a critical regulator of PCV2 nuclear egress and reveal the importance of this finding in circovirus replication.

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Epstein–Barr virus glycoprotein gM can interact with the cellular protein p32 and knockdown of p32 impairs virus

Cited by 11 publications

References 46 publications

Nuclear Egress Complexes of HCMV and Other Herpesviruses: Solving the Puzzle of Sequence Coevolution, Conserved Structures and Subfamily-Spanning Binding Properties

Nuclear Egress Complexes of HCMV and Other Herpesviruses: Solving the Puzzle of Sequence Coevolution, Conserved Structures and Subfamily-Spanning Binding Properties

Patterns of Autologous and Nonautologous Interactions between Core Nuclear Egress Complex (NEC) Proteins of α-, β- and γ-Herpesviruses

Cellular p32 Is a Critical Regulator of Porcine Circovirus Type 2 Nuclear Egress

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