Intracellular localization of the UL31 protein of herpes simplex virus type 2

Zhu, Hongzhen; Yamada, Hiroshi; Jiang, Yue-Mei; Yamada, Masao; Nishiyama, Yukihiro

doi:10.1007/s007050050715

Cited by 38 publications

(37 citation statements)

References 43 publications

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“…The possible existence of so far undefined INM sorting motifs in pUL50 and its homologues should be investigated in the future. In the case of HCMV pUL53, homologues have been described in all herpesvirus subfamilies that attain nuclear localization in the absence of other viral proteins such as pUL50 homologues (Camozzi et al, 2008;Fuchs et al, 2002;Gonnella et al, 2005;Milbradt et al, 2007;Muranyi et al, 2002;Reynolds et al, 2001;Zhu et al, 1999). Interestingly, NLS sequences could be predicted for most of them (Table 1), and in the present study a functional NLS sequence could be characterized for HCMV pUL53.…”

Section: Comparison Of the Mechanisms Of Core Nec Formation In Hcmv Asupporting

confidence: 50%

The cytomegalovirus egress proteins pUL50 and pUL53 are translocated to the nuclear envelope through two distinct modes of nuclear import

Schmeiser

Borst

Sticht

et al. 2013

Journal of General Virology

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The nucleocytoplasmic export of cytomegaloviral capsids is regulated by formation of a multicomponent nuclear egress complex (NEC), essentially based on viral proteins pUL50 and pUL53. In this study, the generation of recombinant human cytomegaloviruses, expressing tagged versions of pUL50 and pUL53, enabled the investigation of NEC formation in infected primary fibroblasts. For these recombinant viruses, a wild-type-like mode of pUL50-pUL53 interaction and recruitment of both proteins to the nuclear envelope could be demonstrated. Importantly, pUL50 was translocated from an initial cytoplasmic distribution to the nuclear rim, whereas pUL53 accumulated in the nucleus before attaining overall rim colocalization with pUL50. Specified experimental settings illustrated that pUL50 and pUL53 were subject to different pathways of intracellular trafficking. Importantly, a novel nuclear localization signal (NLS) could be identified and functionally verified for pUL53 (amino acids 18-27), whereas no NLS was present in pUL50. Analysis of amino acid replacement mutants further illustrated the differential modes of nuclear import of the two essential viral egress proteins. Taken together, our findings suggest a combination of classical nuclear import (pUL53) and interaction-mediated recruitment (pUL50) as the driving forces for core NEC formation and viral nuclear egress.

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Section: Comparison Of the Mechanisms Of Core Nec Formation In Hcmv Asupporting

confidence: 50%

The cytomegalovirus egress proteins pUL50 and pUL53 are translocated to the nuclear envelope through two distinct modes of nuclear import

Schmeiser

Borst

Sticht

et al. 2013

Journal of General Virology

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“…However, for reasons that remain to be elucidated, the kinetics of HSV-2 expression in murine DC was more rapid than previously observed in cells of primate origin (34). Infection of the murine BMDC with either strain appeared to be abortive, as we did not detect any significant increase in the titer of infectious virus released into the supernatant during prolonged culture.…”

Section: Discussionmentioning

confidence: 41%

Herpes Simplex Virus Type 2 Induces Rapid Cell Death and Functional Impairment of Murine Dendritic Cells In Vitro

Jones

Fernandez²,

Herc³

et al. 2003

J Virol

110

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Dendritic cells (DC) are critical for stimulation of naive T cells. Little is known about the effect of herpes simplex virus type 2 (HSV-2) infection on DC structure or function or if the observed effects of HSV-1 on human DC are reproduced in murine DC. Here, we demonstrate that by 12 h postinfection, wild-type (wt) HSV-2 (186) abortively infected murine bone marrow-derived DC and induced early cell death compared to UV-inactivated HSV-2 or mock-infected DC. HSV-2-induced loss of DC viability was more rapid than that induced by HSV-1 and was due, in part, to apoptosis, as shown by TEM, caspase-3 activation, and terminal deoxynucleotidyl transferase-mediated dCTP biotin nick end labeling. HSV induced type-specific changes in the murine DC immunophenotype. At 12 h postinfection, wt HSV-2 upregulated DC major histocompatibility complex (MHC) class II expression, and in contrast to UV-inactivated HSV-2, downregulated expression of MHC class I, but it had no effect on surface CD40, CD80, or CD86. Wt HSV-1 (MC-1) induced only CD40 upregulation. More-profound effects on the DC immunophenotype were observed in HSV-2-infected neonatal DC. Wt HSV of either serotype impaired murine DC-induced T-cell alloproliferation and lipopolysaccharideinduced DC interleukin-12 secretion. Thus, there are marked differences in the levels of HSV-induced cytolysis in DC according to the HSV serotype, although HSV-2 displays immunomodulatory effects on the DC immunophenotype and function similar to those of HSV-1.Dendritic cells (DC) play a key role in the induction of the primary cellular immune response to intracellular pathogens like herpes simplex virus (HSV), as they are the main cell type that stimulates naive T cells in the draining lymph nodes (23). The strength and character of the antigen-specific T-cell response are determined by factors such as the level of costimulatory molecule (B-7) expression and the density of antigen expressed on the surfaces of DC (1, 33). DC are also thought to be the major source of interleukin-12 (IL-12) (31), which has been demonstrated to play a pivotal role in the differentiation of naive CD4 ϩ T cells into type 1 T helper (Th1) cells (18), although recent studies suggest that IL-12 produced by DC is required for optimal T-cell gamma interferon production rather than for CD4 ϩ -T-cell polarization (26). HSV type 1 (HSV-1) infection of adult human DC derived from peripheral blood monocytes (MoDC) has been shown by a number of groups (15,19,27) to impair costimulatory molecule upregulation of immature DC. However, the timing and degree of this impairment and the presence or absence of associated effects on major histocompatibility complex (MHC) class I (MHC-I) and MHC-II molecule expression were different, possibly due to differences in the types of HSV-1 strain used. Infection of immature MoDC with a disabled infectious single-cycle mutant (DISC-HSV-1-GFP) inhibited DC maturation (as shown by downregulation of costimulatory molecules) and induced marked downregulation of MHC-I expression, attributed...

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“…(E) Fluorographic images of lamin-GST pulldowns reacted with full-length U L 31 protein. 35 S-labeled U L 31 protein was expressed in a rabbit reticulocyte lysate and reacted in cold PBS supplemented with 1% Triton X-100 with equal amounts of GST or one of several GST fusion proteins bearing regions of lamin A bound to glutathione Sepharose beads. After extensive washing with the Triton X-100 buffer, the protein mixture was resolved on a 10% acrylamide gel, and fluorographic images were obtained as described in the legend to Fig.…”

Section: Discussionmentioning

confidence: 99%

Conformational Changes in the Nuclear Lamina Induced by Herpes Simplex Virus Type 1 Require Genes U _L 31 and U _L 34

Reynolds

Liang

Baines

2004

J Virol

158

209

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The herpes simplex virus type 1 (HSV-1) U L 31 and U L 34 proteins are dependent on each other for proper targeting to the nuclear membrane and are required for efficient envelopment of nucleocapsids at the inner nuclear membrane. In this work, we show that whereas the solubility of lamins A and C (lamin A/C) was not markedly increased, HSV induced conformational changes in the nuclear lamina of infected cells, as viewed after staining with three different lamin A/C-specific antibodies. In one case, reactivity with a monoclonal antibody that recognizes an epitope in the lamin tail domain was greatly reduced in HSV-infected cells. This apparent HSV-induced epitope masking required both U L 31 and U L 34, but these proteins were not sufficient to mask the epitope in uninfected cells, indicating that other HSV proteins are also required. In the second case, staining with a rabbit polyclonal antibody that primarily recognizes epitopes in the lamin A/C rod domain revealed that U L 34 is required for HSV-induced decreased availability of epitopes for reaction with the antibody, whereas U L 31 protein was dispensable for this effect. Still another polyclonal antibody indicated virtually no difference in lamin A/C staining in infected versus uninfected cells, indicating that the HSVinduced changes are more conformational than the result of lamin depletion at the nuclear rim. Further evidence supporting an interaction between the nuclear lamina and the U L 31/U L 34 protein complex includes the observations that (i) overexpression of the U L 31 protein in uninfected cells was sufficient to relocalize lamin A/C from the nuclear rim into nucleoplasmic aggregates, (ii) overexpression of U L 34 was sufficient to relocalize some lamin A/C into the cytoplasm, and (iii) both U L 31 and U L 34 could directly bind lamin A/C in vitro. These studies suggest that the U L 31 and U L 34 proteins modify the conformation of the nuclear lamina in infected cells, possibly by direct interaction with lamin A/C, and that other proteins are also likely involved. Given that the nuclear lamina potentially excludes nucleocapsids from envelopment sites at the inner nuclear membrane, the lamina alteration may reflect a role of the U L 31/U L 34 protein complex in perturbing the lamina to promote nucleocapsid egress from the nucleus. Alternatively, the data are compatible with a role of the lamina in targeting the U L 31/U L 34 protein complex to the nuclear membrane.The nuclear envelope consists of two leaflets, defined as the inner nuclear membrane and outer nuclear membrane. The perinuclear space, defined as the space between the two leaflets, is continuous with the lumen of the endoplasmic reticulum. A network of predominantly insoluble cellular proteins, the nuclear lamina, lines the nucleoplasmic face of the inner nuclear membrane. The nuclear lamina provides structural support for the nuclear membrane and attachment sites for chromatin. It is also required for a variety of essential cellular functions, including nuclear assembly following mi...

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Intracellular localization of the UL31 protein of herpes simplex virus type 2

Cited by 38 publications

References 43 publications

The cytomegalovirus egress proteins pUL50 and pUL53 are translocated to the nuclear envelope through two distinct modes of nuclear import

The cytomegalovirus egress proteins pUL50 and pUL53 are translocated to the nuclear envelope through two distinct modes of nuclear import

Herpes Simplex Virus Type 2 Induces Rapid Cell Death and Functional Impairment of Murine Dendritic Cells In Vitro

Conformational Changes in the Nuclear Lamina Induced by Herpes Simplex Virus Type 1 Require Genes U _L 31 and U _L 34

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Intracellular localization of the UL31 protein of herpes simplex virus type 2

Cited by 38 publications

References 43 publications

The cytomegalovirus egress proteins pUL50 and pUL53 are translocated to the nuclear envelope through two distinct modes of nuclear import

The cytomegalovirus egress proteins pUL50 and pUL53 are translocated to the nuclear envelope through two distinct modes of nuclear import

Herpes Simplex Virus Type 2 Induces Rapid Cell Death and Functional Impairment of Murine Dendritic Cells In Vitro

Conformational Changes in the Nuclear Lamina Induced by Herpes Simplex Virus Type 1 Require Genes U L 31 and U L 34

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Conformational Changes in the Nuclear Lamina Induced by Herpes Simplex Virus Type 1 Require Genes U _L 31 and U _L 34