The PI3K/Akt pathway inhibits influenza A virus-induced Bax-mediated apoptosis by negatively regulating the JNK pathway via ASK1

Lu, Xinya; Mašić, Aleksandar; Yang, Li; Shin, Yeun-Kyung; Liu, Qiang; Zhou, Yan

doi:10.1099/vir.0.018465-0

Cited by 48 publications

(29 citation statements)

References 40 publications

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“…The NS1 protein was found to play a crucial role in the antiapoptotic pathway through activation of the protein kinase complex PI3K (class I)-AKT (9)(10)(11)(12). Accordingly, delNS1 virus induced accelerated apoptosis in infected cells (13)(14)(15). In the present study, we uncovered a new regulatory loop which links NS1, HA, and M2 with autophagy in infected cells.…”

Section: Discussionmentioning

confidence: 64%

“…Both mechanisms promote survival of cells infected with WT virus. In delNS1 virus-infected cells, both prosurvival mechanisms are reduced due to the lack of NS1 and low expression of its regulatory targets, M2 and HA, which promotes accelerated apoptosis (13)(14)(15). In general, downregulation of autophagy and rapid development of apoptosis occurred in delNS1 virus-infected cells, .5, and 14 h p.i., cellular polypeptides were analyzed by PAGE-WB using antibodies specific for AKTpho, 32K and 18K units of activated caspase 3 (Casp3a 32K, Casp3a 18K), actin, and viral NP and for secondary host species-specific HRP conjugates.…”

Section: Discussionmentioning

confidence: 99%

“…To allow host cell survival and to promote viral replication, apoptosis is downregulated early after infection by the interaction of the PI3K (class I)-AKT complex with the virus protein NS1 (9)(10)(11)(12). As a consequence, rapid apoptosis develops in cells infected with influenza virus lacking the NS1 gene (13)(14)(15). However, when overproduced in transfected cells, NS1 induces apoptosis (16,17).…”

mentioning

confidence: 99%

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Influenza A Virus Proteins NS1 and Hemagglutinin Along with M2 Are Involved in Stimulation of Autophagy in Infected Cells

Жирнов

Klenk²

2013

J Virol

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The NS1 protein of influenza A virus is known to downregulate apoptosis early in infection in order to support virus replication (O. P. Zhirnov, T. E. Konakova, T. Wolff, and H. D. Klenk, J. Virol. 76: [1617][1618][1619][1620][1621][1622][1623][1624][1625] 2002). In the present study, we analyzed the development of autophagy, another mechanism to protect cells from degradation that depends on NS1 expression. To this end, we compared autophagy in cells infected with wild-type (WT) influenza virus and virus lacking the NS1 gene (delNS1 virus). The results show that in WT-infected cells but not in delNS1 virus-infected cells, synthesis of the autophagy marker LC3-II, the lipidated form of microtubule light chain-associated protein LC3, is stimulated and that LC3-II accumulates in a perinuclear zone enriched with double-layered membrane vesicles characteristic of autophagosomes. Transfection experiments revealed that NS1 expressed alone was unable to upregulate autophagy, whereas hemagglutinin (HA) and M2 were. Proteolytic cleavage of HA increased autophagy. Taken together, these observations indicate that NS1 stimulates autophagy indirectly by upregulating the synthesis of HA and M2. Thus, it appears that NS1, besides downregulating apoptosis, is involved in upregulation of autophagy and that it supports the survival of infected cells by both mechanisms. Autophagy is a mechanism that allows cell survival under stress conditions, such as amino acid starvation, energy deprivation, and virus infection (1). It is a constitutive process that involves recycling of cytosolic proteins and organelles by lysosomal degradation and an immune response by virus protein degradation and extracellular presentation of degraded molecules to immune recognition (2, 3). Autophagy thereby provides nutrients for maintenance and repair of vital functions of the host, including immune defense. Autophagy is mediated by autophagosomes, specialized double-membrane vesicles originating from the Golgi apparatus, endoplasmic reticulum, and mitochondria, and it is regulated by the interaction of more than 30 autophagy-related cellular genes (Atgs) (4). Two stages can be discriminated in the autophagy process: an initial stage of autophagosome formation and a terminal effector stage (maturation) involving fusion of autophagosomes with lysosomes and degradation of the intra-autophagosomal content. Phosphatidylinositol-3-kinase class III (PI3K-III), beclin (Atg6), and LC3 (Atg8) are important factors involved in autophagy (5). Viruses have developed strategies either to counteract autophagy or to employ the autophagic pathway for their own benefit (1, 3).Influenza A virus modulates autophagy (6-8) as well as apoptosis, another pathway regulating survival of infected cells (8). To allow host cell survival and to promote viral replication, apoptosis is downregulated early after infection by the interaction of the PI3K (class I)-AKT complex with the virus protein NS1 (9-12). As a consequence, rapid apoptosis develops in cells infected with influenza vir...

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Influenza A Virus Proteins NS1 and Hemagglutinin Along with M2 Are Involved in Stimulation of Autophagy in Infected Cells

Жирнов

Klenk²

2013

J Virol

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“…The advantage of this strategy is that it can avoid the emergence of drug-resistant virus strains due to the fact that the target of the drug is a host factor(s) which is not affected by virus mutation [19][20][21].…”

Section: Introductionmentioning

confidence: 99%

Antiviral activity and possible mechanisms of action of pentagalloylglucose (PGG) against influenza A virus

et al. 2011

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Influenza A virus (IAV) infection is a major public health threat leading to significant morbidity and mortality. The emergence of drug-resistant virus strains highlights urgent needs to develop novel antiviral drugs with alternative modes of action. Pentagalloyl glucose (PGG), a natural occuring polyphenolic compound, possesses broad spectrum of biological activities. In this study, we found PGG has anti-influenza virus activity and investigated its possible mechanism(s) of action in vitro.

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“…In the present study, we found that the early signal transmitted by the PI3K/Akt pathway upon PCV2 infection does not require active replication of PCV2. Therefore, as described for other viruses, such as poliovirus (3) and influenza A virus (33), the early transient activation of the PI3K/Akt pathway triggered by PCV2 infection might contribute to JNK-and p38-mediated apoptotic responses in the PCV2-infected cells. However, the underlying mechanism regarding this matter needs further study.…”

Section: Discussionmentioning

confidence: 99%

Activation of the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway during Porcine Circovirus Type 2 Infection Facilitates Cell Survival and Viral Replication

Zhu

Wang

et al. 2012

J Virol

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Virus infection activates host cellular signaling pathways, including the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which regulates diverse cellular activities related to cell growth, survival, and apoptosis. The present study demonstrated for the first time that porcine circovirus type 2 (PCV2), a major causative agent of postweaning multisystemic wasting syndrome, which is an emerging and important swine disease, can transiently induce the PI3K/Akt pathway in cultured cells at an early step during PCV2 infection. Activation of the PI3K/Akt signal was also induced by UV-irradiated PCV2, indicating that virus replication was not required for this induction. Inhibition of PI3K activation leads to reduced virus yield, which is associated with decreased viral DNA replication and lower virus protein expression. However, inhibition of PI3K activation greatly enhanced apoptotic responses as evidenced by the cleavage of poly-ADP ribose polymerase and caspase-3 as well as DNA fragmentation using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling staining during the early stage of PCV2 infection. Furthermore, the pancaspase inhibitor zVAD.fmk alleviated the reduction in Akt phosphorylation levels by inhibiting PI3K activation, indicating that the signaling promotes cell survival and thereby favors viral replication. These results reveal that an antiapoptotic role for the PI3K/Akt pathway induced by PCV2 infection to suppress premature apoptosis for improved virus growth after infection, extending our understanding of the molecular mechanism of PCV2 infection.

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The PI3K/Akt pathway inhibits influenza A virus-induced Bax-mediated apoptosis by negatively regulating the JNK pathway via ASK1

Cited by 48 publications

References 40 publications

Influenza A Virus Proteins NS1 and Hemagglutinin Along with M2 Are Involved in Stimulation of Autophagy in Infected Cells

Influenza A Virus Proteins NS1 and Hemagglutinin Along with M2 Are Involved in Stimulation of Autophagy in Infected Cells

Antiviral activity and possible mechanisms of action of pentagalloylglucose (PGG) against influenza A virus

Activation of the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway during Porcine Circovirus Type 2 Infection Facilitates Cell Survival and Viral Replication

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