Suppression of Extracellular Signal-Regulated Kinase Activity in Herpes Simplex Virus 1-Infected Cells by the Us3 Protein Kinase

Chuluunbaatar, Uyanga; Roller, Richard J.; Mohr, Ian

doi:10.1128/jvi.00622-12

Cited by 35 publications

(32 citation statements)

References 57 publications

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“…Kaposi's sarcoma-associated herpesvirus activates ERK and PI3K through engagement of viral glycoprotein gB with host integrin receptors to stabilize MTs within minutes of infection (9). In contrast, HSV-1 Us3 suppresses both ERK and PI3K-Akt activity (33,35,36). Furthermore, specific downstream substrates such as GSK3β are regulated independent of host PI3K-Akt signaling and are, instead, directly controlled by Us3 (21,33,37,38).…”

Section: Discussionmentioning

confidence: 99%

Plus-end tracking proteins, CLASPs, and a viral Akt mimic regulate herpesvirus-induced stable microtubule formation and virus spread

Naghavi

Gundersen

Walsh

2013

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

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Although microtubules (MTs) frequently form highly dynamic networks, subsets of MTs become stabilized in response to environmental cues and function as specialized tracks for vesicle and macromolecular trafficking. MT stabilization is controlled by specialized plus-end tracking proteins (+TIPs) whose accumulation at the MT ends is facilitated by the end-binding protein, EB1, and regulated by various signaling pathways. As cargoes themselves, viruses are dependent on MTs for their intracellular movement. Although many viruses affect MT organization, the potential contribution of MT stabilization by +TIPs to infection remains unknown. Here we show that early in infection of primary human fibroblasts, herpes simplex virus type 1 (HSV-1) disrupts the centrosome, the primary MT organizing center in many cell types. As infection progresses HSV-1 induces the formation of stable MT subsets through inactivation of glycogen synthase kinase 3beta by the viral Ser/Thr kinase, Us3. Stable MT formation is reduced in cells infected with Us3 mutants and those stable MTs that form cluster around the trans-Golgi network. Downstream of glycogen synthase kinase 3beta, cytoplasmic linker-associated proteins (CLASPs), specialized host +TIPs that control MT formation at the trans-Golgi network and cortical capture, are specifically required for virus-induced MT stabilization and HSV-1 spread. Our findings demonstrate the biological importance of +TIPs to viral infection and suggest that HSV-1 has evolved to exploit the trans-Golgi network as an alternate MT organizing center to facilitate virus spread.M icrotubules (MTs) function in a variety of processes, including directed intracellular trafficking of cargos and changes in cell shape, polarity, and motility (1, 2). Consisting of polarized heteropolymers of α/β-tubulin, in most cells MT minusends are anchored at the perinuclear MT organizing center (MTOC), whereas their plus-ends radiate toward the cell periphery. In proliferating cells, the majority of MTs are highly dynamic, growing and shrinking through the addition or loss of tubulin subunits primarily at the plus-end. Dynamic instability facilitates intracellular sensing through "search-and-capture." On encountering targets such as the cell cortex and in response to specific signals, subsets of MTs become stabilized and acquire posttranslational modifications such as acetylation and detyrosination (3). Stable MTs are recognized by specific motor proteins and act as specialized tracks for vesicle transport (1, 3). MT stabilization is mediated by proteins that track dynamic MT plusends and influence rates of MT growth, pause, and collapse, known as plus-end tracking proteins (+TIPs) (4). Central to plusend tracking is EB1, a member of the end-binding family of proteins that recognizes growing MT ends. Although many +TIPs are capable of associating with MTs, it is their interaction with EB1 that mediates their specific accumulation at MT plus-ends (4). +TIP activity and interaction with EB1 responds to signals including Rho-Dia act...

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Section: Discussionmentioning

confidence: 99%

Plus-end tracking proteins, CLASPs, and a viral Akt mimic regulate herpesvirus-induced stable microtubule formation and virus spread

Naghavi

Gundersen

Walsh

2013

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

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“…The interaction between alphaherpesviruses and ERK1/2 signaling has been studied extensively for the past years (17)(18)(19)(20)(21)23). This signaling axis controls various fundamental cellular events, making it an attractive target for the virus to subvert the host, promoting viral replication and survival.…”

Section: Discussionmentioning

confidence: 99%

“…It may come as no surprise that many viruses, including alphaherpesviruses, modulate the ERK1/2 signaling pathway (17)(18)(19)(20)(21).…”

mentioning

confidence: 99%

Pseudorabies Virus Triggers Glycoprotein gE-Mediated ERK1/2 Activation and ERK1/2-Dependent Migratory Behavior in T Cells

Pontes

Devriendt

Favoreel

2015

J Virol

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The interaction between viruses and immune cells of the host may lead to modulation of intracellular signaling pathways and to subsequent changes in cellular behavior that are of benefit for either virus or host. ERK1/2 (extracellular signal regulated kinase 1/2) signaling represents one of the key cellular signaling axes. Here, using wild-type and gE null virus, recombinant gE, and gEtransfected cells, we show that the gE glycoprotein of the porcine Varicellovirus pseudorabies virus (PRV) triggers ERK1/2 phosphorylation in Jurkat T cells and primary porcine T lymphocytes. PRV-induced ERK1/2 signaling resulted in homotypic T cell aggregation and increased motility of T lymphocytes. Our study reveals a new function of the gE glycoprotein of PRV and suggests that PRV, through activation of ERK1/2 signaling, has a substantial impact on T cell behavior. IMPORTANCEHerpesviruses are known to be highly successful in evading the immune system of their hosts, subverting signaling pathways of the host to their own advantage. The ERK1/2 signaling pathway, being involved in many cellular processes, represents a particularly attractive target for viral manipulation. Glycoprotein E (gE) is an important virulence factor of alphaherpesviruses, involved in viral spread. In this study, we show that gE has the previously uncharacterized ability to trigger ERK1/2 phosphorylation in T lymphocytes. We also show that virus-induced ERK1/2 signaling leads to increased migratory behavior of T cells and that migratory T cells can spread the infection to susceptible cells. In conclusion, our results point to a novel function for gE and suggest that virus-induced ERK1/2 activation may trigger PRV-carrying T lymphocytes to migrate and infect other cells susceptible to PRV replication.A lphaherpesviruses constitute the largest subfamily of the herpesviruses. This subfamily contains closely related pathogens, including herpes simplex virus 1 (HSV-1), HSV-2, and varicellazoster virus (VZV) in humans. Another member of the alphaherpesvirus subfamily is the porcine pseudorabies virus (PRV), which is often used as a model to study general features of alphaherpesvirus biology (1).PRV encodes 11 glycoproteins (2) incorporated in the viral envelope, which are embedded in different host membranes of the infected cell, including the plasma membrane. One of these glycoproteins is glycoprotein E (gE), which is important for virulence and viral (neuronal) spread (3-10). For both PRV and HSV-1, there are indications that gE may have a signaling function in immune cells, as it drives signaling-dependent processes like cell surface antigen capping (11-13). However, to date, there are no reports that gE indeed triggers any particular signaling pathway.The extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signaling pathway is an evolutionarily conserved pathway, controlling many fundamental cellular events, such as cell proliferation, survival, differentiation, migration, apoptosis, and metabolism (14-16). It ma...

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“…It acts by phosphorylating a number of viral and cellular substrates, including UL47 (28), UL34 (29), histone deacetylases 1 and 2 (30)(31)(32), lamin A/C (33), and Bad (34). Functions ascribed to US3 include preventing apoptosis (35)(36)(37)(38)(39)(40)(41), enhancing viral gene expression by inhibiting histone deacetylation (32,42,43), promoting nuclear egress of progeny nucleocapsids (44)(45)(46)(47)(48), stimulating viral cell-to-cell spread (49)(50)(51), evading the immune system (52-55), modulating membrane biosynthesis (56), and downregulating extracellular signal-regulated kinase (ERK) activity (57). Relevant to the present report, Akt activation is enhanced during US3-null infection (16), suggesting that US3 also negatively regulates Akt during HSV-1 infection.…”

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confidence: 99%

Herpes Simplex Virus Protein Kinases US3 and UL13 Modulate VP11/12 Phosphorylation, Virion Packaging, and Phosphatidylinositol 3-Kinase/Akt Signaling Activity

Eaton

Saffran

et al. 2014

J Virol

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The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway plays key roles in diverse cellular activities and promotes cell growth and survival. It is therefore unsurprising that most viruses modify this pathway in order to facilitate their replication and spread. Previous work has suggested that the herpes simplex virus 1 (HSV-1) tegument proteins VP11/12 and US3 protein kinase modulate the PI3K/Akt pathway, albeit in opposing ways: VP11/12 binds and activates Src family kinases (SFKs), is tyrosine phosphorylated, recruits PI3K in an SFK-dependent fashion, and is required for HSV-induced phosphorylation of Akt on its activating residues; in contrast, US3 inhibits Akt activation and directly phosphorylates downstream Akt targets. We examined if US3 negatively regulates Akt by dampening the signaling activity of VP11/12. Consistent with this hypothesis, the enhanced Akt activation that occurs during US3-null infection requires VP11/12 and correlates with an increase in SFK-dependent VP11/12 tyrosine phosphorylation. In addition, deleting US3 leads to a striking increase in the relative abundances of several VP11/12 species that migrate with reduced mobility during SDS-PAGE. These forms arise through phosphorylation, strictly require the viral UL13 protein kinase, and are excluded from virions. Taken in combination, these data indicate that US3 dampens SFK-dependent tyrosine and UL13-dependent serine/threonine phosphorylation of VP11/12, thereby inhibiting VP11/12 signaling and promoting virion packaging of VP11/12. These results illustrate that protein phosphorylation events mediated by viral protein kinases serve to coordinate the roles of VP11/12 as a virion component and intracellular signaling molecule. IMPORTANCEHerpesvirus tegument proteins play dual roles during the viral life cycle, serving both as structural components of the virus particle and as modulators of cellular and viral functions in infected cells. How these two roles are coordinated during infection and virion assembly is a fundamental and largely unanswered question. Here we addressed this issue with herpes simplex virus VP11/12, a tegument protein that activates the cellular PI3K/Akt signaling pathway. We showed that protein phosphorylation mediated by the viral US3 and UL13 kinases serves to orchestrate its functions: UL13 appears to inhibit VP11/12 virion packaging, while US3 antagonizes UL13 action and independently dampens VP11/12 signaling activity.

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Suppression of Extracellular Signal-Regulated Kinase Activity in Herpes Simplex Virus 1-Infected Cells by the Us3 Protein Kinase

Cited by 35 publications

References 57 publications

Plus-end tracking proteins, CLASPs, and a viral Akt mimic regulate herpesvirus-induced stable microtubule formation and virus spread

Plus-end tracking proteins, CLASPs, and a viral Akt mimic regulate herpesvirus-induced stable microtubule formation and virus spread

Pseudorabies Virus Triggers Glycoprotein gE-Mediated ERK1/2 Activation and ERK1/2-Dependent Migratory Behavior in T Cells

Herpes Simplex Virus Protein Kinases US3 and UL13 Modulate VP11/12 Phosphorylation, Virion Packaging, and Phosphatidylinositol 3-Kinase/Akt Signaling Activity

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