Protein Kinase B/Akt Is Present in Activated Form throughout the Entire Replicative Cycle of ΔU<sub>S</sub>3 Mutant Virus but Only at Early Times after Infection with Wild-Type Herpes Simplex Virus 1

Benetti, Luca; Roizman, Bernard

doi:10.1128/jvi.80.7.3341-3348.2006

Cited by 67 publications

(61 citation statements)

References 49 publications

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“…Previous reports have shown that R7041-infected cells showed enhanced Akt phosphorylation/activation compared with R7306 wild-type-infected cells (31). Our results showed that whereas R7306 infection minimally (in U87 cells) or moderately (in A549 cells) induced Akt phosphorylation, R7041 infection strongly induced Akt activation (Fig.…”

Section: Resultssupporting

confidence: 48%

Herpes Simplex Virus Us3(−) Mutant as Oncolytic Strategy and Synergizes with Phosphatidylinositol 3-Kinase-Akt–Targeting Molecular Therapeutics

Liu

Wakimoto

Martuza

et al. 2007

Clinical Cancer Research

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Purpose: Oncolytic herpes simplex virus (HSV) vectors have shown safety in clinical trials, but efficacy remains unsatisfactory. Novel HSV vectors that possess tumor selectivity with enhanced potency are therefore needed. The gene product of HSV Us3 protects virus-infected cells from apoptosis, a cellular pathway frequently dysfunctional in tumors. We hypothesized that Us3 mutants, whose replication would be inhibited by apoptosis in normal cells, would be selective for tumor cells. Experimental Design: HSV mutants G207 (ribonucleotide reductase -/g34.5 -), R7041 (Us3 -), and R7306 (Us3 revertant) were tested in normal and tumor cells for viral replication, antitumoral potency, apoptosis induction, and Akt activation. Safety and biodistribution after systemic administration and antitumoral efficacy after intratumoral (i.t.) or i.v. administration were examined. Results: Us3 deletion results in up to 3-log replication inhibition in normal cells, which correlates with enhanced apoptosis induction. In contrast, R7041 replicates very well in tumor cells, showing 1 to 2 log greater yield than G207. In vivo, R7041 shows no signs of toxicity after systemic delivery in both immunocompetent and immunodeficient mice and shows preferential and prolonged replication in tumors compared with normal tissues. R7041 displays significant antitumoral efficacy after i.t. or i.v. administration. An additional feature of Us3 mutants is enhanced Akt activation compared with wild-type infection, which sensitizes cells to phosphatidylinositol 3-kinase-Akt inhibitors (LY294002, Akt inhibitor IV), shown by synergistic antitumoral activity in vitro and enhanced efficacy in vivo. Conclusions: Us3 deletion confers enhanced tumor selectivity and antitumoral potency on herpes simplex virus-1and provides for a novel mechanism of combination therapy with phosphatidylinositol 3-kinase-Akt^targeting molecular therapeutics.

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Section: Resultssupporting

confidence: 48%

Herpes Simplex Virus Us3(−) Mutant as Oncolytic Strategy and Synergizes with Phosphatidylinositol 3-Kinase-Akt–Targeting Molecular Therapeutics

Liu

Wakimoto

Martuza

et al. 2007

Clinical Cancer Research

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“…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%

“…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%

“…infection in many cell lines, is important for efficient anterograde movement and HSV-1 spread in vivo and in specific cell types, notably including NHDFs (21,22,(31)(32)(33)(34). In terms of cytoskeletal regulation, a number of its properties potentially position Us3 as a central regulator of host MTs that may underlie differences with other viral strategies.…”

Section: Discussionmentioning

confidence: 99%

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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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“…These findings support the matching of MDD groups S2 and T2 with CK2 group. With regard to PKB which is matched with cluster S4, it is reported to be involved in the regulation of the Herpes Simplex virus -1 [25]. Additionally, experimental research also claims that PKB signaling benefits coxsackie virus B3 replication [26].…”

Section: Motifs Comparisonmentioning

confidence: 99%

Exploiting Two-Layered Support Vector Machine to Predict Phosphorylation Sites on Virus Proteins

Lu¹,

Bretaña²,

Chang³

et al. 2013

IJBBB

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Abstract-Protein phosphorylation in viruses plays crucial regulatory roles in enhancing progression, replication, and inhibition of host cell functions. Due to the difficulty of mass spectrometry-based identification of viral phosphorylation sites, we are motivated to develop a new method to investigate the substrate motifs and identify protein phosphorylation sites on viruses. The experimentally verified phosphorylation data were extracted from a public resource and a recursively statistical method is applied to cluster whole data set of phosphorylated sequences into subgroups containing remarkably sequence motifs around the phosphorylation sites. Two-layered Support Vector Machine (SVM) is then applied to learn a predictive model by integrating the detected sequence motifs. A five-fold cross validation evaluation on the SVM model yields an average accuracy of 0.88 for Serine and 0.83 for Threonine. Furthermore, the independent testing data collected from UniProtKB and Phospho.ELM indicates that the proposed method is comparable with three popular kinase-specific phosphorylation site prediction tools. The cross validation and independent testing demonstrated that the sequence motifs are informative for the prediction of potential kinases for virus protein phosphorylation sites. Furthermore, the proposed method is a practical means of preliminary analysis for virus phosphorylation dynamics.Index Terms-Virus, protein phosphorylation, substrate motif, support vector machine.

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Protein Kinase B/Akt Is Present in Activated Form throughout the Entire Replicative Cycle of ΔU_S3 Mutant Virus but Only at Early Times after Infection with Wild-Type Herpes Simplex Virus 1

Cited by 67 publications

References 49 publications

Herpes Simplex Virus Us3(−) Mutant as Oncolytic Strategy and Synergizes with Phosphatidylinositol 3-Kinase-Akt–Targeting Molecular Therapeutics

Herpes Simplex Virus Us3(−) Mutant as Oncolytic Strategy and Synergizes with Phosphatidylinositol 3-Kinase-Akt–Targeting Molecular Therapeutics

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

Exploiting Two-Layered Support Vector Machine to Predict Phosphorylation Sites on Virus Proteins

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Protein Kinase B/Akt Is Present in Activated Form throughout the Entire Replicative Cycle of ΔUS3 Mutant Virus but Only at Early Times after Infection with Wild-Type Herpes Simplex Virus 1

Cited by 67 publications

References 49 publications

Herpes Simplex Virus Us3(−) Mutant as Oncolytic Strategy and Synergizes with Phosphatidylinositol 3-Kinase-Akt–Targeting Molecular Therapeutics

Herpes Simplex Virus Us3(−) Mutant as Oncolytic Strategy and Synergizes with Phosphatidylinositol 3-Kinase-Akt–Targeting Molecular Therapeutics

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

Exploiting Two-Layered Support Vector Machine to Predict Phosphorylation Sites on Virus Proteins

Contact Info

Product

Resources

About

Protein Kinase B/Akt Is Present in Activated Form throughout the Entire Replicative Cycle of ΔU_S3 Mutant Virus but Only at Early Times after Infection with Wild-Type Herpes Simplex Virus 1