The Herpes Simplex Virus Protein pUL31 Escorts Nucleocapsids to Sites of Nuclear Egress, a Process Coordinated by Its N-Terminal Domain

Funk, Christina; Ott, Mélanie; Raschbichler, Verena; Nagel, Claus-Henning; Binz, Anne; Sodeik, Beate; Bauerfeind, Rudolf; Bailer, Susanne M.

doi:10.1371/journal.ppat.1004957

Cited by 65 publications

(116 citation statements)

References 72 publications

(188 reference statements)

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“…Previous analyses of biochemical properties pointed to a tightly interlocked high-affinity heterodimer formed between pUL50 and pUL53, similar to the respective homologs of other herpesviruses (9,19,30,31). A mutational analysis of the protein segments that participate in the pUL50-pUL53 interaction supported this notion, namely that a unique type of interlock is provided by N-terminal ␣-helical segments of pUL53 that become tightly hooked into a platform provided by pUL50.…”

Section: Resultsmentioning

confidence: 92%

Crystal Structure of the Human Cytomegalovirus pUL50-pUL53 Core Nuclear Egress Complex Provides Insight into a Unique Assembly Scaffold for Virus-Host Protein Interactions

Walzer

Egerer-Sieber

Sticht

et al. 2015

Journal of Biological Chemistry

139

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Background:The conserved cytomegalovirus proteins pUL50 and pUL53 heterodimerize and form a core nuclear egress complex. Results: The crystal structure of pUL50-pUL53 was solved at 2.44 Å resolution, revealing an N-terminal hooklike extension of pUL53. Conclusion: Data unravel the core NEC architecture, providing a scaffold for viral-cellular NEC protein interactions. Significance: The identified NEC structure will stimulate the development of novel antiviral strategies.

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Section: Resultsmentioning

confidence: 92%

Crystal Structure of the Human Cytomegalovirus pUL50-pUL53 Core Nuclear Egress Complex Provides Insight into a Unique Assembly Scaffold for Virus-Host Protein Interactions

Walzer

Egerer-Sieber

Sticht

et al. 2015

Journal of Biological Chemistry

139

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“…HSV-1 UL31 protein is a multi-functional nucleoprotein, which is transported into the nucleus via Ran-, transportin-1-and importin α1-mediated pathway [19], and this nuclear accumulation is important for viral infection [55]. Meanwhile, HSV-1 UL31 and its homologue EBV BFLF2 are both crucial for efficient viral DNA packaging and primary egress across the nuclear membrane [18].…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Nucleocytoplasmic Transport Mechanisms of Epstein-Barr Virus BFLF2

Chen

Zou

et al. 2018

Cell Physiol Biochem

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Background/Aims: Epstein-Barr virus (EBV) BFLF2, the homologue of herpes simplex virus 1 (HSV-1) UL31, is crucial for the efficient viral DNA packaging and primary egress across the nuclear membrane. However, we still do not know its subcellular transport mechanisms. Methods: Interspecies heterokaryon assays were utilized to detect the nucleocytoplasmic shuttling of BFLF2, and mutation analysis, plasmid transfection and fluorescence microscopy assays were performed to identify the functional nuclear localization sequence (NLS) and nuclear export sequence (NES) of BFLF2 in live cells. Furthermore, the nuclear import and export of BFLF2 were assessed by confocal microscopy, co-immunoprecipitation and immunoblot assays. Results: BFLF2 was confirmed to shuttle between the nucleus and cytoplasm. Two predicted NESs were shown to be nonfunctional, yet we proved that the nuclear export of BFLF2 was mediated through transporter associated with antigen processing (TAP), but not chromosomal region maintenance 1 (CRM1) dependent pathway. Furthermore, one functional NLS, ²²RRLMHPHHRNYTASKASAH⁴⁰, was identified, and the aa22-23, aa22-25, aa28-30 and aa37-40 had an important role in the nuclear localization of BFLF2. Besides, the nuclear import of BFLF2 was demonstrated through Ran-, importin α7-, importin β1- and transportin-1-dependent mechanism that does not require importin α1, α3 and α5. Conclusion: These works are of significance for the further study of the functions of BFLF2 during EBV infection, as well as for further insights into the design of new antiviral drug target and vaccine development against EBV.

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“…Recent reports (40,47) have suggested that nuclear egress is a two-part process: First, UL31, the soluble partner of the nuclear egress complex (PRV, Uniprot Q7TBN7), binds capsids in the nucleoplasm. Afterward, UL31 acts an adapter that mediates binding to UL34, the membrane-bound partner of the nuclear egress complex (PRV, Uniprot G3G8X8).…”

Section: Discussionmentioning

confidence: 99%

Remodeling nuclear architecture allows efficient transport of herpesvirus capsids by diffusion

Bosse

Hogue

Feric

et al. 2015

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

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100

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The nuclear chromatin structure confines the movement of large macromolecular complexes to interchromatin corrals. Herpesvirus capsids of approximately 125 nm assemble in the nucleoplasm and must reach the nuclear membranes for egress. Previous studies concluded that nuclear herpesvirus capsid motility is active, directed, and based on nuclear filamentous actin, suggesting that large nuclear complexes need metabolic energy to escape nuclear entrapment. However, this hypothesis has recently been challenged. Commonly used microscopy techniques do not allow the imaging of rapid nuclear particle motility with sufficient spatiotemporal resolution. Here, we use a rotating, oblique light sheet, which we dubbed a ring-sheet, to image and track viral capsids with high temporal and spatial resolution. We do not find any evidence for directed transport. Instead, infection with different herpesviruses induced an enlargement of interchromatin domains and allowed particles to diffuse unrestricted over longer distances, thereby facilitating nuclear egress for a larger fraction of capsids.he nucleus is structured into chromatin and interchromatin compartments, giving it a "sponge-like" appearance, with the chromatin representing the actual sponge material and the interchromatin regions representing the enclosed pores, tubes, tunnels, and cisterna. This conceptual model has important implications for how differently sized molecules could move inside the nucleus. Although small molecules like GFP, streptavidin, fluorescent dextrans, or mRNA can mostly freely diffuse throughout the nucleus (1-3), large macromolecular assemblies, such as 100-nm fluorescent beads and promyelocytic leukemia (PML) or Cajal bodies, are trapped in interchromatin spaces called corrals. These corrals slowly move as a result of chromatin dynamics, and particles can also escape over long time scales (4, 5). Herpesvirus capsids of 125-nm diameter are assembled in the nucleus and must move to the nuclear periphery to exit the nucleus by budding through the nuclear membranes (6). Similarly, large host cargo like ribonucleoprotein (RNP) particles may need to move through the nucleus before they exit the nucleus in the same way (7). Earlier, we and others provided data that suggested that herpesvirus capsids use an active, directed mechanism based on F-actin to transport through the nucleoplasm (8, 9) and/or that nuclear F-actin is involved in capsid assembly. However, we recently showed that herpesviruses do not induce nuclear F-actin in most cells, and, more importantly, that nuclear capsid motility is not dependent on nuclear F-actin (10). This led us to reinvestigate nuclear capsid motility by single particle tracking to address whether molecular motors power it.During herpesvirus infection, the interchromatin domains enlarge and the nuclear volume increases as much as twofold (11). At the same time, viral replication compartments expand, move, and coalesce, but do not mix (12-16). By using a light-sheet modality we dubbed a ring-sheet, we were able to trace...

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The Herpes Simplex Virus Protein pUL31 Escorts Nucleocapsids to Sites of Nuclear Egress, a Process Coordinated by Its N-Terminal Domain

Cited by 65 publications

References 72 publications

Crystal Structure of the Human Cytomegalovirus pUL50-pUL53 Core Nuclear Egress Complex Provides Insight into a Unique Assembly Scaffold for Virus-Host Protein Interactions

Crystal Structure of the Human Cytomegalovirus pUL50-pUL53 Core Nuclear Egress Complex Provides Insight into a Unique Assembly Scaffold for Virus-Host Protein Interactions

Characterization of the Nucleocytoplasmic Transport Mechanisms of Epstein-Barr Virus BFLF2

Remodeling nuclear architecture allows efficient transport of herpesvirus capsids by diffusion

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