Avian influenza A virus H5N1 causes autophagy-mediated cell death through suppression of mTOR signaling

Ma, Jiguang; Sun, Qian; Mi, Ruifang; Zhang, Hongbing

doi:10.1016/j.jgg.2011.10.002

Cited by 86 publications

(85 citation statements)

References 26 publications

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“…For instance, autophagy-related proteins, including Beclin 1, Atg4B, Atg5, and Atg12, are required for initiation of hepatitis C virus (HCV) replication (28). In addition, avian influenza A H5N1 virus and avian reovirus trigger autophagy through suppression of mTOR signaling (31,32).…”

Section: Discussionmentioning

confidence: 99%

Autophagy Benefits the Replication of Newcastle Disease Virus in Chicken Cells and Tissues

Sun

Ding

et al. 2014

J Virol

102

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bNewcastle disease virus (NDV) is an important avian pathogen. We previously reported that NDV triggers autophagy in U251 glioma cells, resulting in enhanced virus replication. In this study, we investigated whether NDV triggers autophagy in chicken cells and tissues to enhance virus replication. We demonstrated that NDV infection induced steady-state autophagy in chickenderived DF-1 cells and in primary chicken embryo fibroblast (CEF) cells, evident through increased double-or single-membrane vesicles, the accumulation of green fluorescent protein (GFP)-LC3 dots, and the conversion of LC3-I to LC3-II. In addition, we measured autophagic flux by monitoring p62/SQSTM1 degradation, LC3-II turnover, and GFP-LC3 lysosomal delivery and proteolysis, to confirm that NDV infection induced the complete autophagic process. Inhibition of autophagy by pharmacological inhibitors and RNA interference reduced virus replication, indicating an important role for autophagy in NDV infection. Furthermore, we conducted in vivo experiments and observed the conversion of LC3-I to LC3-II in heart, liver, spleen, lung, and kidney of NDV-infected chickens. Regulation of the induction of autophagy with wortmannin, chloroquine, or starvation treatment affects NDV production and pathogenesis in tissues of both lung and intestine; however, treatment with rapamycin, an autophagy inducer of mammalian cells, showed no detectable changes in chicken cells and tissues. Moreover, administration of the autophagy inhibitor wortmannin increased the survival rate of NDV-infected chickens. Our studies provide strong evidence that NDV infection induces autophagy which benefits NDV replication in chicken cells and tissues.

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Section: Discussionmentioning

confidence: 99%

Autophagy Benefits the Replication of Newcastle Disease Virus in Chicken Cells and Tissues

Sun

Ding

et al. 2014

J Virol

102

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“…Thus, it seems likely that the AKT-mTOR pathway loop has a negligible influence on the generation of autophagosomes in H1N1-infected cells, irrespective of whether or not NS1 is expressed. However, the AKT-mTOR pathway may be involved in the downregulation of autophagy in cells infected with H5N1 virus (31,32). Moreover, HAs of highly pathogenic viruses H5 and H7, unlike those of low-pathogenic viruses of subtypes H1, H3, H9, etc., were found here to possess a strong capacity for autophagy stimulation due to their membrane-associated furindependent cleavage within cells.…”

Section: Fig 7 Ns1-dependent Regulatory Links Between Autophagy and Amentioning

confidence: 99%

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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“…31 This "selfeating" process exerts important roles in many aspects of physiology and pathology, including intracellular homeostasis, cell death, tumor suppression, and aging. 32,33 Recently, it has been reported that induction of autophagy is frequently observed in many human cancer cell lines treated with chemotherapeutics. [34][35][36] However, whether autophagy induced by chemotherapy acts as a protective mechanism that allows treated cancer cells to survive or rather as an alternative cell death-inducing process has been an issue of great controversy.…”

Section: Introductionmentioning

confidence: 99%

MTOR inhibition attenuates DNA damage and apoptosis through autophagy-mediated suppression of CREB1

Wang

Liu

et al. 2013

Autophagy

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Avian influenza A virus H5N1 causes autophagy-mediated cell death through suppression of mTOR signaling

Cited by 86 publications

References 26 publications

Autophagy Benefits the Replication of Newcastle Disease Virus in Chicken Cells and Tissues

Autophagy Benefits the Replication of Newcastle Disease Virus in Chicken Cells and Tissues

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

MTOR inhibition attenuates DNA damage and apoptosis through autophagy-mediated suppression of CREB1

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