Torsin Mediates Primary Envelopment of Large Ribonucleoprotein Granules at the Nuclear Envelope

Jokhi, Vahbiz; Ashley, James A.; Nunnari, John J.; Noma, Akiko; Ito, Naoto; Wakabayashi-Ito, Noriko; Moore, Melissa J.; Budnik, Vivian

doi:10.1016/j.celrep.2013.03.015

Cited by 141 publications

(243 citation statements)

References 36 publications

(53 reference statements)

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“…Although nuclear egress was once thought to be limited to herpesviruses, recently, a broadly similar process has been identified for the export of ribonucleoprotein complexes in Drosophila (18,40), suggesting that insight into herpesvirus nuclear egress may be more generally applicable than previously thought. Still, the unusual structure presented here of a crucial player in nuclear egress underscores the unusual nature of this process.…”

Section: Significancementioning

confidence: 92%

Structure of a herpesvirus nuclear egress complex subunit reveals an interaction groove that is essential for viral replication

Leigh

Sharma

Mansueto

et al. 2015

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

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Herpesviruses require a nuclear egress complex (NEC) for efficient transit of nucleocapsids from the nucleus to the cytoplasm. The NEC orchestrates multiple steps during herpesvirus nuclear egress, including disruption of nuclear lamina and particle budding through the inner nuclear membrane. In the important human pathogen human cytomegalovirus (HCMV), this complex consists of nuclear membrane protein UL50, and nucleoplasmic protein UL53, which is recruited to the nuclear membrane through its interaction with UL50. Here, we present an NMR-determined solution-state structure of the murine CMV homolog of UL50 (M50; residues 1-168) with a strikingly intricate protein fold that is matched by no other known protein folds in its entirety. Using NMR methods, we mapped the interaction of M50 with a highly conserved UL53-derived peptide, corresponding to a segment that is required for heterodimerization. The UL53 peptide binding site mapped onto an M50 surface groove, which harbors a large cavity. Point mutations of UL50 residues corresponding to surface residues in the characterized M50 heterodimerization interface substantially decreased UL50-UL53 binding in vitro, eliminated UL50-UL53 colocalization, prevented disruption of nuclear lamina, and halted productive virus replication in HCMV-infected cells. Our results provide detailed structural information on a key protein-protein interaction involved in nuclear egress and suggest that NEC subunit interactions can be an attractive drug target.H erpesviruses encompass a large family of infectious agents, including important veterinary and human pathogens (1). Among the latter is human cytomegalovirus (HCMV), which can cause serious disease, particularly in immunocompromised individuals and newborns (2). Despite the importance of HCMV in these medically vulnerable populations, currently available treatment options suffer from issues with toxicities, drug resistance, and/or pharmacokinetics (2, 3), motivating the identification of new drug targets.All herpesviruses of mammals, birds, and reptiles undergo a remarkable process known as nuclear egress as part of the viral lifecycle. It is generally accepted that, after assembly in the nucleus, the viral nucleocapsid undergoes envelopment to cross the inner nuclear membrane (INM) followed by deenvelopment to cross the outer nuclear membrane, resulting in release into the cytoplasm for continuation of the virion maturation process (4). Nuclear egress is orchestrated by a highly conserved, heterodimeric nuclear egress complex (NEC), which recruits one or more protein kinases to disrupt the nuclear lamina, permitting access of nucleocapsids to the INM, where the NEC induces budding of the nucleocapsid into the perinuclear space (5-13). In HCMV, the NEC is comprised of UL50, which is an INM protein, and UL53, which is a nucleoplasmic protein that is brought to the INM by its interaction with UL50. These two proteins and their murine CMV (MCMV) homologues, M50 and M53, are essential for replication and nuclear egress (8, 14-17) of ...

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Section: Significancementioning

confidence: 92%

Structure of a herpesvirus nuclear egress complex subunit reveals an interaction groove that is essential for viral replication

Leigh

Sharma

Mansueto

et al. 2015

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

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“…Viruses typically act by usurping normal cellular processes, suggesting a function for trans-membrane nuclear transport independent of the normal nuclear pore-based route. In drosophila, torsinA has been linked to the formation of such structures implicated in the transport of ribonucleoprotein granules [80,81], whereas in mouse these torsinA-related structures have been linked to the transport of nuclear ubiquitinated nuclear proteins [71].…”

Section: Torsina Functionmentioning

confidence: 99%

Inherited Isolated Dystonia: Clinical Genetics and Gene Function

Dauer

2014

Neurotherapeutics

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“…Once through the lamina, capsids must traverse the nuclear membrane in a process now thought to be similar to the passage of large ribonucleoprotein particles from the nucleus to the cytoplasm (Jokhi et al, 2013;Speese et al, 2012). Briefly, capsids must bud through the inner leaflet of the nuclear membrane into the intramembrane space.…”

Section: Exit Of Capsids From the Nucleus: The Nuclear Laminamentioning

confidence: 99%

“…In HSV-infected cells, this process is governed by the interaction of the nuclear egress complex and capsid proteins (Yang & Baines, 2011). A similar mechanism may operate in HCMV-infected cells.Once through the lamina, capsids must traverse the nuclear membrane in a process now thought to be similar to the passage of large ribonucleoprotein particles from the nucleus to the cytoplasm (Jokhi et al, 2013;Speese et al, 2012). Briefly, capsids must bud through the inner leaflet of the nuclear membrane into the intramembrane space.…”

mentioning

confidence: 99%

Viral and cellular subnuclear structures in human cytomegalovirus-infected cells

Strang

2015

Journal of General Virology

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In human cytomegalovirus (HCMV)-infected cells, a dramatic remodelling of the nuclear architecture is linked to the creation, utilization and manipulation of subnuclear structures. This review outlines the involvement of several viral and cellular subnuclear structures in areas of HCMV replication and virus-host interaction that include viral transcription, viral DNA synthesis and the production of DNA-filled viral capsids. The structures discussed include those that promote or impede HCMV replication (such as viral replication compartments and promyelocytic leukaemia nuclear bodies, respectively) and those whose role in the infected cell is unclear (for example, nucleoli and nuclear speckles). Viral and cellular proteins associated with subnuclear structures are also discussed. The data reviewed here highlight advances in our understanding of HCMV biology and emphasize the complexity of HCMV replication and virus-host interactions in the nucleus. IntroductionThe betaherpesvirus human cytomegalovirus (HCMV) is a widespread opportunistic pathogen that severely affects immunocompromised and immunodeficient populations (Mocarski et al., 2007). Like all herpesviruses, HCMV undergoes either productive or latent infection. During productive infection, infectious virus is produced, while in latent infection the virus becomes largely transcriptionally quiescent (Mocarski et al., 2007). Like other herpesviruses, many events that are critical for productive HCMV replication take place within the nucleus. These include essential steps in viral replication, such as: the transcriptional cascade of immediate-early (IE), early and late viral RNA transcripts, synthesis of viral DNA and the production of DNA-containing capsids (Mocarski et al., 2007). Compared with the prototype human herpesvirus, the alphaherpesvirus herpes simplex virus (HSV), certain features of productive HCMV infection are not well characterized. However, it is clear that several subnuclear structures are involved in HCMV genome replication and virus-host interactions. Uncovering the roles of these structures has led to significant advances in our understanding of HCMV biology. This review summarizes the involvement of several viral and cellular subnuclear structures in productive HCMV infection. The participation of each structure in HCMV replication and virus-host interactions is described from entry of the viral genome into the nucleus to the egress of viral capsids through the nuclear membrane. The data discussed highlight recent advances in our understanding of subnuclear structure function, introduce viral and cellular factors associated with subnuclear structures and indicate what questions have yet to be answered.Entry of the HCMV genome into the nucleus: the nuclear pore complex, nuclear speckles, promyelocytic leukaemia protein nuclear bodies and pp150 bodies HCMV genome entry into the nucleus is poorly defined but may be similar to movement of the HSV DNA genome through the nuclear pore complex (NPC) (Kobiler et al., 2012) (Fig. 1a). HCMV capsid ...

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Torsin Mediates Primary Envelopment of Large Ribonucleoprotein Granules at the Nuclear Envelope

Cited by 141 publications

References 36 publications

Structure of a herpesvirus nuclear egress complex subunit reveals an interaction groove that is essential for viral replication

Structure of a herpesvirus nuclear egress complex subunit reveals an interaction groove that is essential for viral replication

Inherited Isolated Dystonia: Clinical Genetics and Gene Function

Viral and cellular subnuclear structures in human cytomegalovirus-infected cells

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