Herpes Simplex Virus Requires VP11/12 To Activate Src Family Kinase-Phosphoinositide 3-Kinase-Akt Signaling

Wagner, Melany J.; Smiley, James R.

doi:10.1128/jvi.01877-10

Cited by 43 publications

(65 citation statements)

References 80 publications

(87 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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). Here, we find that Us3 induces MT acetylation in transfected cells and is required for efficient stable MT formation in infected cells.…”

Section: Discussionmentioning

confidence: 62%

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.

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 62%

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.

View full text Add to dashboard Cite

show abstract

“…HSV also induces phosphorylation of GSK-3␣/␤ but through the US3 protein kinase (38). While HSV VP11/12 and VZV ORF12 protein both activate PI3K/Akt, HSV VP11/12 does not activate GSK-3␤ (23). In addition, while VZV ORF12 protein phosphorylates ERK and Akt, HSV VP11/12 only activates Akt.…”

Section: Discussionmentioning

confidence: 95%

“…Many viral proteins that activate the PI3K/Akt pathway either form a complex with the p85 regulatory subunit of PI3K (e.g., influenza A virus NS1 protein [24], bursal disease virus VP5 [25], HSV-1 VP11/12 [23]) or activate kinases upstream of Akt, such as Skp1 (myxoma virus M-T5 protein [26]) or Ras (EBV LMP2A [11], HSV-2 ICP10PK [27]). Some viral proteins directly associate with Akt (e.g., NS1 of influenza A virus [28], HBx protein of hepatitis B virus [29], or M-T5 protein of myxoma virus [30]).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Varicella-Zoster Virus ORF12 Protein Activates the Phosphatidylinositol 3-Kinase/Akt Pathway To Regulate Cell Cycle Progression

Liu

Cohen

2013

J Virol

View full text Add to dashboard Cite

show abstract

“…Two tegument proteins have been shown to modulate PI3K/ Akt activity during HSV-1 infection: the US3 serine/threonine protein kinase (16) and the VP11/12 protein, encoded by the gene UL46 (17,18). Benetti and Roizman showed that HSV-1 infection leads to activation of Akt in a PI3K-dependent fashion (16), and Wagner and Smiley later showed that this effect strictly requires VP11/12 (18), a highly abundant (between 1,000 and 2,000 copies) tegument phosphoprotein (19,20).…”

mentioning

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Herpes Simplex Virus Requires VP11/12 To Activate Src Family Kinase-Phosphoinositide 3-Kinase-Akt Signaling

Cited by 43 publications

References 80 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

Varicella-Zoster Virus ORF12 Protein Activates the Phosphatidylinositol 3-Kinase/Akt Pathway To Regulate Cell Cycle Progression

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

Contact Info

Product

Resources

About