Rotavirus Nonstructural Protein 1 Suppresses Virus-Induced Cellular Apoptosis To Facilitate Viral Growth by Activating the Cell Survival Pathways during Early Stages of Infection

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b p53, a member of the innate immune system, is triggered under stress to induce cell growth arrest and apoptosis. Thus, p53 is an important target for viruses, as efficient infection depends on modulation of the host apoptotic machinery. This study focuses on how rotaviruses manipulate intricate p53 signaling for their advantage. Analysis of p53 expression revealed degradation of p53 during initial stages of rotavirus infection. However, in nonstructural protein-1 (NSP1) mutant strain A5-16, p53 degradation was not observed, suggesting a role of NSP1 in this process. This function of NSP1 was independent of its interferon or phosphatidylinositol 3-kinase (PI3K)/AKT modulation activity since p53 degradation was observed in Vero cells as well as in the presence of PI3K inhibitor. p53 transcript levels remained the same in SA11-infected cells (at 2 to 14 h postinfection), but p53 protein was stabilized only in the presence of MG132, suggesting a posttranslational process. NSP1 interacted with the DNA binding domain of p53, resulting in ubiquitination and proteasomal degradation of p53. Degradation of p53 during initial stages of infection inhibited apoptosis, as the proapoptotic genes PUMA and Bax were downregulated. During late viral infection, when progeny dissemination is the main objective, the NSP1-p53 interaction was diminished, resulting in restoration of the p53 level, with initiation of proapoptotic signaling ensuing. Overall results highlight the multiple strategies evolved by NSP1 to combat the host immune response.

mentioning

confidence: 99%

Rotavirus-Encoded Nonstructural Protein 1 Modulates Cellular Apoptotic Machinery by Targeting Tumor Suppressor Protein p53

Bhowmick

Halder

Chattopadhyay

et al. 2013

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“…Infected host cells undergo apoptosis to limit viral propagation (25). Therefore, many viruses carry antiapoptotic factors to facilitate replication, such as poliovirus (29), rotavirus (30), influenza virus (31,32), dengue virus (33), infectious bursal disease virus (34), and cowpox virus (35). To determine , 25 m).…”

Section: Pcv2-infected Cells Express the Orf4-encoded Protein In Vitrmentioning

confidence: 99%

Identification and Functional Analysis of the Novel ORF4 Protein Encoded by Porcine Circovirus Type 2

Cao

Zhou

et al. 2013

116

bPorcine circovirus type 2 (PCV2) is the primary causative agent of porcine circovirus-associated diseases in pigs. To date, viral proteins Cap, Rep, Rep=, and ORF3, encoded by the PCV2 genome, have been described. Here, transcription and translation of a novel viral gene within the PCV2 genome (designated ORF4) was determined and functionally analyzed in vitro and in vivo. Northern blot analysis indicated that the RNA transcribed from the ORF4 gene is about 180 bp in length and overlaps ORF3 in the same direction. Site-directed mutagenesis confirmed that the viral ORF4 protein is not essential for virus replication in PK-15 cells and in mice infected with an ORF4-deficient PCV2 (PCV2⌬). PCV2⌬ triggered higher activity levels of caspase-3 and -8 than wild-type PCV2 (wPCV2) in PK-15 cells. The antigenic epitopes of two mouse monoclonal antibodies (MAbs) raised against the viral ORF4 protein were mapped to the same 19KSSASPR25 peptide. Expression of ORF4 was confirmed using the specific MAbs in wPCV2-infected PK-15 cells and mice. Mice infected with PCV2⌬ had a higher serum viral load (genomic copies) and more severe lymphoid tissue damage in the spleen than those infected with wPCV2. Meanwhile, flow-cytometric analysis indicated that the PCV2⌬ infection caused a significant decrease of CD4 ؉ and CD8 ؉ T lymphocytes. Our results demonstrate that ORF4 is a newly discovered viral protein that is not essential for PCV2 replication but plays a role in suppressing caspase activity and regulating CD4؉ and CD8 ؉ T lymphocytes during PCV2 infection.

“…Virtually all viruses regulate this pathway either positively or negatively in order to create a favorable environment for their survival and spread. To these ends, viruses use diverse strategies, including producing proteins that mimic an activated cell surface receptor (polyoma middle T antigen [9]), directly interact with PI3K (NSP1 of rotavirus [10]) or Akt (M-T 5 of myxoma virus [11]), inactivate Akt (vesicular stomatitis virus matrix protein [12]), or mimic Akt (vAKT from mammalian AKT8 retrovirus [13]). …”

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

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.