Autophagic machinery activated by dengue virus enhances virus replication

Lee, Ying‐Ray; Lei, Huan Yao; Liu, Ming Tao; Wang, Jen Ren; Chen, Shun Hua; Jiang-Shieh, Ya Fen; Lin, Yee Shin; Yeh, Trai Ming; Liu, Ching Chuan; Liu, Hsiao Sheng

doi:10.1016/j.virol.2008.02.016

Cited by 320 publications

(342 citation statements)

References 27 publications

(40 reference statements)

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“…Although flavivirus induces apoptosis of neurons and macrophages, infected hepatocytes and epithelial cells do not die. We find that flavivirus up-regulates autophagy in MDCK 3 renal epithelial cells and other cell types and subsequently protects them. We further identify nonstructural protein NS4A of both Dengue-2 and Modoc viruses as the sole viral mediator of autophagy up-regulation and protection against death.…”

mentioning

confidence: 75%

“…Flaviviruses often persist in liver and kidney following the acute phase of infection, suggesting that infected cells evade destruction by the host immune response, likely by flavivirusinduced up-regulation of autophagy in these cells. In vitro infection of hepatocytes and fibroblasts leads to up-regulation in autophagy and protection against death (3,4). More relevant, Dengue-2 viruses replicate within the hepatocyte autophagosomes (5), and inhibition of autophagy attenuates virus replication (3).…”

mentioning

confidence: 99%

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Flavivirus NS4A-induced Autophagy Protects Cells against Death and Enhances Virus Replication

McLean

Wudzinska

Datan

et al. 2011

Journal of Biological Chemistry

222

223

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Over 2.5 billion people live in areas at high risk for Dengue and related flavivirus infections (1). Dengue hemorrhagic fever, a severe complication present in ϳ5% of cases, claims more lives annually than all other hemorrhagic fevers combined (2); much of the damage is caused by death of infected cells. The fate of infected cells depends on cell type. Although flavivirus induces apoptosis of neurons and macrophages, infected hepatocytes and epithelial cells do not die. We find that flavivirus up-regulates autophagy in MDCK 3 renal epithelial cells and other cell types and subsequently protects them. We further identify nonstructural protein NS4A of both Dengue-2 and Modoc viruses as the sole viral mediator of autophagy up-regulation and protection against death. Up-regulation of autophagosomes by either live virus infection or NS4A expression depends on PI3K and is important for replication of flavivirus in renal epithelial cells. Flaviviruses often persist in liver and kidney following the acute phase of infection, suggesting that infected cells evade destruction by the host immune response, likely by flavivirusinduced up-regulation of autophagy in these cells. In vitro infection of hepatocytes and fibroblasts leads to up-regulation in autophagy and protection against death (3, 4). More relevant, Dengue-2 viruses replicate within the hepatocyte autophagosomes (5), and inhibition of autophagy attenuates virus replication (3). We extend these findings by identifying the nonstructural viral protein NS4A as the virus-encoded protein that up-regulates autophagy and thus protects the host cell against death, providing a well protected host cell for long term replication of virus.The flavivirus genome contains 10 genes encoding an ϳ11-kDa polyprotein precursor that binds to the ER membrane after translation at the rough ER as follows: three structural proteins (capsid (core) protein, pre-membrane protein ,and envelope glycoprotein) and seven nonstructural genes (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) that mediate viral replication, assembly, and evasion of the host immune system. The active proteins are cleaved from the ER-bound viral polyprotein by cellular proteases signalase and furin and viral protease NS3/ 2B. NS3 is both a viral protease (with required cofactor NS2B (6)) and a viral ATP-dependent helicase (7, 8); NS5 is an RNAdependent RNA polymerase and methyltransferase (9) responsible for virus genome replication, whereas NS1 is possibly a part of the viral replication complex (10). The small hydrophobic flavivirus proteins (NS2A, NS4A, and NS4B) remain the most poorly characterized. NS2A is required for the assembly of new flavivirus virions; NS4A associates with the virus replication complex and induces ER membrane rearrangements (discussed below), and NS4B is an antagonist of interferon. Flavivirus NS4A is an ϳ16-kDa membrane-associated protein consisting of four transmembrane helices and an N-terminal cytosolic region. Once the viral genome is translated in the ER,

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confidence: 75%

mentioning

confidence: 99%

Flavivirus NS4A-induced Autophagy Protects Cells against Death and Enhances Virus Replication

McLean

Wudzinska

Datan

et al. 2011

Journal of Biological Chemistry

222

223

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“…A distinct example is dengue virus (DENV), a virus in the Flavivirus genus and therefore more closely related to HCV. DENV infection has been shown to induce autophagy which promotes viral replication (Lee et al, 2008). Furthermore, it was observed that the DENV NS1 protein and dsRNA (as markers of replication complexes) colocalized with LC3, the ribosomal protein L28 and the mannose 6-phosphate receptor, suggesting that the DENV replication/translation machinery is present on amphisomes, which result from the fusion of autophagosomes and endosomes (Panyasrivanit et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Early events in the generation of autophagosomes are required for the formation of membrane structures involved in hepatitis C virus genome replication

Mohl

Bartlett

Mankouri

et al. 2016

Journal of General Virology

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Hepatitis C virus (HCV) infection has been shown to induce autophagy but the mechanisms underpinning this process remain to be elucidated. Induction of autophagy requires the class III phosphatidylinositol 3-kinase, Vps34, which produces phosphatidylinositol 3-phosphate (PI3P) within the endoplasmic reticulum (ER) membrane. This recruits proteins with PI3P binding domains such as the double-FYVE-containing protein 1 (DFCP1). DFCP1 generates cupshaped protrusions from the ER membrane, termed omegasomes, which provide a platform for the production of autophagosomes. Here we present data demonstrating that both Vps34 and DFCP1 are required for HCV genome replication, in the context of both a subgenomic replicon and virus infection, but did not affect virus entry or initial translation. Using live cell fluorescence microscopy we demonstrated that early during HCV infection the nascent viral genome replication complexes (identified by using non-structural protein NS5A as a marker) transiently colocalize with DFCP1-positive punctae (omegasomes), before the two structures move apart from each other. This observation is reminiscent of the transient association of LC3 and DFCP1 during omegasome formation, and therefore we propose that omegasomes are utilized by HCV to generate the double-membrane vesicles which are the hallmark of HCV replication complexes.

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“…The enhanced activation of autophagy by rapidly replicating bacteria such as wBm during larval development and in adult worm populations and induced by wMelPop in Drosophila also may influence the successful infection and transmission of viruses. For example, the requirement of arboviruses (Dengue and Chikungunya) for an intact host autophagy system and their use of autophagosomes for successful replication and transmission (34,35) may be blocked by Wolbachia-mediated manipulation of autophagosomal maturation, a hypothesis we are testing currently.…”

Section: Discussionmentioning

confidence: 99%

Autophagy regulates Wolbachia populations across diverse symbiotic associations

Voronin

Cook

Steven

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

110

109

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Wolbachia are widespread and abundant intracellular symbionts of arthropods and filarial nematodes. Their symbiotic relationships encompass obligate mutualism, commensalism, parasitism, and pathogenicity. A consequence of these diverse associations is that Wolbachia encounter a wide range of host cells and intracellular immune defense mechanisms of invertebrates, which they must evade to maintain their populations and spread to new hosts. Here we show that autophagy, a conserved intracellular defense mechanism and regulator of cell homeostasis, is a major immune recognition and regulatory process that determines the size of Wolbachia populations. The regulation of Wolbachia populations by autophagy occurs across all distinct symbiotic relationships and can be manipulated either chemically or genetically to modulate the Wolbachia population load. The recognition and activation of host autophagy is particularly apparent in rapidly replicating strains of Wolbachia found in somatic tissues of Drosophila and filarial nematodes. In filarial nematodes, which host a mutualistic association with Wolbachia, the use of antibiotics such as doxycycline to eliminate Wolbachia has emerged as a promising approach to their treatment and control. Here we show that the activation of host nematode autophagy reduces bacterial loads to the same magnitude as antibiotic therapy; thus we identify a bactericidal mode of action targeting Wolbachia that can be exploited for the development of chemotherapeutic agents against onchocerciasis, lymphatic filariasis, and heartworm.Brugia malayi | innate immunity | chemotherapy | helminth | endosymbiont W olbachia is a widespread and abundant endosymbiotic bacterium of arthropods and filarial nematodes that resides in vacuoles of host germline and somatic cells. Wolbachia show a diverse variety of symbiotic associations with their host, ranging from obligate mutualism in filarial nematodes to commensal, parasitic, or pathogenic associations in insects and other arthropod hosts (1-5).In filarial nematodes Wolbachia is obligatory for normal larval growth and development, embryogenesis, and survival of adult worms (1). Although the molecular basis of this mutualistic relationship remains unknown, a comparison of host and bacterial genomes suggests that intact biosynthetic pathways for haem, nucleotides, riboflavin, and FAD may be among the contributions of the bacteria to the biology of the nematode host (6-8). The biological processes most sensitive to Wolbachia loss include larval growth and development and embryogenesis in adult females. These processes have a high metabolic demand because of the rapid growth, development, and organogenesis of the nematode and are associated with the rapid expansion of Wolbachia populations following larval infection of mammalian hosts and in reproductively active adult females (9). Loss of Wolbachia results in extensive apoptosis of germline and somatic cells of embryos, microfilariae, and fourth-stage (L4) larvae, presumably because of the lack of provision of ...

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Autophagic machinery activated by dengue virus enhances virus replication

Cited by 320 publications

References 27 publications

Flavivirus NS4A-induced Autophagy Protects Cells against Death and Enhances Virus Replication

Flavivirus NS4A-induced Autophagy Protects Cells against Death and Enhances Virus Replication

Early events in the generation of autophagosomes are required for the formation of membrane structures involved in hepatitis C virus genome replication

Autophagy regulates Wolbachia populations across diverse symbiotic associations

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