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Halford, William P.; Weisend, Carla; Grace, J.; Soboleski, Mark R.; Carr, Daniel J.J.; Balliet, John W.; Imai, Yumi; Margolis, Todd P.; Gebhardt, Bryan M.

doi:10.1186/1743-422x-3-44

Cited by 87 publications

(67 citation statements)

References 65 publications

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“…For example, although HSV-1 lacking the virion host shutoff protein vhs replicates to wild-type levels in cultured cells, it is highly attenuated in mice (93). Similarly, depletion of STAT1 does not affect HSV-1 replication in culture (94), but it renders mice highly susceptible to infection in vivo (95)(96)(97)(98)(99)(100). Furthermore, high levels of WDR11 are found in the brains of embryonic and adult mice (35), and disruptions to WDR11 are associated with IHH/KS/CPHD (35,38), conditions that result from abnormal migration of specific neurons during embryogenesis (reviewed in reference 101).…”

Section: Discussionmentioning

confidence: 99%

Cellular Protein WDR11 Interacts with Specific Herpes Simplex Virus Proteins at thetrans-Golgi Network To Promote Virus Replication

Taylor

Mossman

2015

J Virol

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It has recently been proposed that the herpes simplex virus (HSV) protein ICP0 has cytoplasmic roles in blocking antiviral signaling and in promoting viral replication in addition to its well-known proteasome-dependent functions in the nucleus. However, the mechanisms through which it produces these effects remain unclear. While investigating this further, we identified a novel cytoplasmic interaction between ICP0 and the poorly characterized cellular protein WDR11. During an HSV infection, WDR11 undergoes a dramatic change in localization at late times in the viral replication cycle, moving from defined perinuclear structures to a dispersed cytoplasmic distribution. While this relocation was not observed during infection with viruses other than HSV-1 and correlated with efficient HSV-1 replication, the redistribution was found to occur independently of ICP0 expression, instead requiring viral late gene expression. We demonstrate for the first time that WDR11 is localized to the transGolgi network (TGN), where it interacts specifically with some, but not all, HSV virion components, in addition to ICP0. Knockdown of WDR11 in cultured human cells resulted in a modest but consistent decrease in yields of both wild-type and ICP0-null viruses, in the supernatant and cell-associated fractions, without affecting viral gene expression. Although further study is required, we propose that WDR11 participates in viral assembly and/or secondary envelopment. IMPORTANCEWhile the TGN has been proposed to be the major site of HSV-1 secondary envelopment, this process is incompletely understood, and in particular, the role of cellular TGN components in this pathway is unknown. Additionally, little is known about the cellular functions of WDR11, although the disruption of this protein has been implicated in multiple human diseases. Therefore, our finding that WDR11 is a TGN-resident protein that interacts with specific viral proteins to enhance viral yields improves both our understanding of basic cellular biology as well as how this protein is co-opted by HSV. W ith worldwide seroprevalence rates reaching 60 to 90% (1), herpes simplex virus 1 (HSV-1) is a tremendously successful human pathogen. HSV-1 particles consist of a double-stranded DNA genome encased by an icosahedral capsid, surrounded by a proteinaceous layer known as the tegument, which is in turn enclosed by an envelope of host-derived lipids (2). During the lytic replication cycle, viral glycoprotein-mediated fusion of the envelope with the host cell plasma membrane releases the capsid and tegument proteins into the cytosol (3). HSV capsids are then transported to the nucleus along microtubules via molecular motor proteins (4). The release of the genome into the nucleus is followed by viral gene expression in a sequential manner, beginning with the immediate-early (IE) genes and then progressing to the early (E) and late (L) classes, resulting in viral genomic DNA replication and packaging into capsids.Although subsequent steps have been controversial, it is n...

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Section: Discussionmentioning

confidence: 99%

Cellular Protein WDR11 Interacts with Specific Herpes Simplex Virus Proteins at thetrans-Golgi Network To Promote Virus Replication

Taylor

Mossman

2015

J Virol

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“…Conversely, IRF3-deficient mice survive intravenous infection with wild-type HSV-1 (101) and show no increased viral replication in peripheral tissues (101)(102)(103), though augmented replication was observed in the central nervous system (102,103). While ICP0-null mutants are attenuated in wild-type mice (96,104,105), viruses lacking ICP0 have not been studied in IRF3-deficient mice. Here, we used IRF3 Ϫ/Ϫ mice to investigate the replication of our ICP0 mutants, using an intravaginal model of infection, as HSV-1 is now responsible for at least 50% of new genital herpes episodes in developed countries (reviewed in reference 106).…”

Section: Discussionmentioning

confidence: 99%

Novel Roles of Cytoplasmic ICP0: Proteasome-Independent Functions of the RING Finger Are Required To Block Interferon-Stimulated Gene Production but Not To Promote Viral Replication

Taylor

Chew

Ashkar

et al. 2014

J Virol

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The immediate-early protein ICP0 from herpes simplex virus 1 (HSV-1) plays pleiotropic roles in promoting viral lytic replication and reactivation from latency. Most of the known actions of ICP0 occur in the nucleus and are thought to involve the E3 ubiquitin ligase activity of its RING finger domain, which targets proteins for degradation via the proteasome. Although ICP0 translocates to the cytoplasm as the infection progresses, little is known about its activities in this location. Here, we show that cytoplasmic ICP0 has two distinct functions. In primary cell cultures and in an intravaginal mouse model, cytoplasmic ICP0 promotes viral replication in the absence of an intact RING finger domain. Additionally, ICP0 blocks the activation of interferon regulatory factor 3 (IRF3), a key transcription factor of the innate antiviral response, in a mechanism that requires the RING finger domain but not the proteasome. To our knowledge, this is the first observation of a proteasome-independent function of the RING finger domain of ICP0. Collectively, these results underscore the importance of cytoplasm-localized ICP0 and the diverse nature of its activities. IMPORTANCEDespite ICP0 being a well-studied viral protein, the significance of its cytoplasmic localization has been largely overlooked. This is, in part, because common experimental manipulations result in the restriction of ICP0 to the nucleus. By overcoming this constraint, we both further characterize the ability of cytoplasmic ICP0 to inhibit antiviral signaling and show that ICP0 at this site has unexpected activities in promoting viral replication. This demonstrates the importance of considering location when analyzing protein function and adds a new perspective to our understanding of this multifaceted protein.

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“…Most of our current knowledge about the role of T cells and their cytokines in preventing ␣-herpesvirus reactivation from sensory neurons has been obtained from mouse studies (9)(10)(11)(12)(13)(14). Because of the species restriction of VZV susceptibility, these studies have been limited to HSV-1.…”

Section: H Erpes Simplex Virus (Hsv) and Varicella Zoster Virus (Vzv)mentioning

confidence: 99%

Selective retention of herpes simplex virus-specific T cells in latently infected human trigeminal ganglia

Verjans¹,

Hintzen

Dun

et al. 2007

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

198

227

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Untitled

Cited by 87 publications

References 65 publications

Cellular Protein WDR11 Interacts with Specific Herpes Simplex Virus Proteins at thetrans-Golgi Network To Promote Virus Replication

Cellular Protein WDR11 Interacts with Specific Herpes Simplex Virus Proteins at thetrans-Golgi Network To Promote Virus Replication

Novel Roles of Cytoplasmic ICP0: Proteasome-Independent Functions of the RING Finger Are Required To Block Interferon-Stimulated Gene Production but Not To Promote Viral Replication

Selective retention of herpes simplex virus-specific T cells in latently infected human trigeminal ganglia

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