Significance of host cell kinases in herpes simplex virus type 1 egress and lamin-associated protein disassembly from the nuclear lamina

Program in Molecular and Cellular Biology, University of Iowa, Iowa City, IA 52242, USA.
Virology (Impact Factor: 3.32). 10/2010; 406(1):127-37. DOI: 10.1016/j.virol.2010.07.002
Source: PubMed

ABSTRACT The nuclear lamina is thought to be a steric barrier to the herpesvirus capsid. Disruption of the lamina accompanied by phosphorylation of lamina proteins is a conserved feature of herpesvirus infection. In HSV-1-infected cells, protein kinase C (PKC) alpha and delta isoforms are recruited to the nuclear membrane and PKC delta has been implicated in phosphorylation of emerin and lamin B. We tested two critical hypotheses about the mechanism and significance of lamina disruption. First, we show that chemical inhibition of all PKC isoforms reduced viral growth five-fold and inhibited capsid egress from the nucleus. However, specific inhibition of either conventional PKCs or PKC delta does not inhibit viral growth. Second, we show hyperphosphorylation of emerin by viral and cellular kinases is required for its disassociation from the lamina. These data support hypothesis that phosphorylation of lamina components mediates lamina disruption during HSV nuclear egress.

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    • "During HSV-1 replication it has been described that UL34 recruits US3 viral kinase and PKC-delta, inducing hyperphosphorylation of emerin and altering lamins. Moreover, it is well documented that a second viral kinase, UL13, phosphorylates US3 in infected cells and regulates UL34 and UL31 localization (Kato et al., 2006; Leach and Roller, 2010; Mou et al., 2009). Otherwise, gamma herpesviruses show a different behavior: during EBV lytic replication, the viral kinase BGLF4, homolog to UL13, targets the nucleus through interaction with nucleoporin and induces disassembly of the nuclear lamina (Lee et al., 2008). "
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    ABSTRACT: p29, a newly identified Kaposi's sarcoma-associated herpesvirus (KSHV) protein, is the product of ORF67, the positional homolog of the conserved herpesvirus protein UL34. Like its homologues in other herpesviruses, p29 is expressed early during viral lytic cycle, and is localized on the nuclear rim. Upon chemical induction of viral replication in primary effusion lymphoma cells, p29 interacts with p33, encoded by ORF69, the positional homolog of the conserved herpesvirus protein UL31, and both proteins colocalize on the nuclear membrane. IFA and biochemical analysis of infected or transfected cells showed that p29 expression resulted in delocalization and hyperphosphorylation of emerin, whereas other nuclear lamin associated proteins, such as LUMA, LB1 and LBR were not affected. Mislocalization of emerin was robustly increased upon combined expression of p29 and p33, suggesting that emerin destabilization might represent the first step in nuclear lamina disassembling, a process necessary for nucleocapsid maturation.
    Virus Research 04/2013; 175(2). DOI:10.1016/j.virusres.2013.04.001 · 2.32 Impact Factor
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    • "Atypical Protein Kinase C Is Required for DFz2C/LamC Foci Formation HSV nucleocapsids recruit a host protein kinase C (PKC), which phosphorylates A-and B-type lamin, disrupting the nuclear Cell 149, 832–846, May 11, 2012 ª2012 Elsevier Inc. 837 lamina at the INM and allowing the capsid to bud into the perinuclear space (Park and Baines, 2006). The PKC involved in this process is likely not a conventional PKC (Leach and Roller, 2010). Notably, we observed that a binding partner of Drosophila atypical PKC (aPKC), Bazooka (Baz)/Par3, colocalized with LamC, both in the nuclear lamina and at foci (Figure 6A). "
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    ABSTRACT: Localized protein synthesis requires assembly and transport of translationally silenced ribonucleoprotein particles (RNPs), some of which are exceptionally large. Where in the cell such large RNP granules first assemble was heretofore unknown. We previously reported that during synapse development, a fragment of the Wnt-1 receptor, DFrizzled2, enters postsynaptic nuclei where it forms prominent foci. Here we show that these foci constitute large RNP granules harboring synaptic protein transcripts. These granules exit the nucleus by budding through the inner and the outer nuclear membranes in a nuclear egress mechanism akin to that of herpes viruses. This budding involves phosphorylation of A-type lamin, a protein linked to muscular dystrophies. Thus nuclear envelope budding is an endogenous nuclear export pathway for large RNP granules.
    Cell 05/2012; 149(4):832-46. DOI:10.1016/j.cell.2012.03.032 · 32.24 Impact Factor
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    • "Dephosphorylation of lamin B is elicited by PP1 and it is linked to assembly of the nuclear lamina at the end of mitosis [Steen and Collas, 2001]. Importantly, lamin B, as well as lamin A/C and emerin, can be also phosphorylated during viral infections, a mechanism allowing breakdown of the lamina and representing a potential target of anti-viral therapy [Jacque and Stevenson, 2006; Camozzi et al., 2008; Leach and Roller, 2010]. The CaaX box of B type lamins is farnesylated. "
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    ABSTRACT: Laminopathies are genetic diseases due to mutations or altered post-translational processing of nuclear envelope/lamina proteins. The majority of laminopathies are caused by mutations in the LMNA gene, encoding lamin A/C, but manifest as diverse pathologies including muscular dystrophy, lipodystrophy, neuropathy, and progeroid syndromes. Lamin-binding proteins implicated in laminopathies include lamin B2, nuclear envelope proteins such as emerin, MAN1, LBR, and nesprins, the nuclear matrix protein matrin 3, the lamina-associated polypeptide, LAP2alpha and the transcriptional regulator FHL1. Thus, the altered functionality of a nuclear proteins network appears to be involved in the onset of laminopathic diseases. The functional interplay among different proteins involved in this network implies signaling partners. The signaling effectors may either modify nuclear envelope proteins and their binding properties, or use nuclear envelope/lamina proteins as platforms to regulate signal transduction. In this review, both aspects of lamin-linked signaling are presented and the major pathways so far implicated in laminopathies are summarized.
    Journal of Cellular Biochemistry 04/2011; 112(4):979-92. DOI:10.1002/jcb.22992 · 3.26 Impact Factor
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