Cholesterol-rich lipid rafts are required for release of infectious human respiratory syncytial virus particles

Chang, Te-Hung; Segovia, Jesus A.; Sabbah, Ahmed; Mgbemena, Victoria; Bose, Santanu

doi:10.1016/j.virol.2011.10.029

Cited by 54 publications

(58 citation statements)

References 52 publications

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“…Beyond entry, cell membrane cholesterol is also required for the synthesis of several viruses. Cholesterol-enriched lipid rafts in cell membranes play a role in the formation of replication compartments and in the assembly and budding of several enveloped viruses (14)(15)(16)(17)(18)(19)(20)(21). Beyond its role in West Nile virus (WNV) entry, the postentry replication of the WNV infectious strain NY385-99 is independent of cell cholesterol (22).…”

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confidence: 99%

Cellular Cholesterol Facilitates the Postentry Replication Cycle of Herpes Simplex Virus 1

Wudiri

Nicola

2017

J Virol

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Cholesterol is an essential component of cell membranes and is required for herpes simplex virus 1 (HSV-1) entry (1-3). Treatment of HSV-1-infected Vero cells with methyl beta-cyclodextrin from 2 to 9 h postentry reduced plaque numbers. Transport of incoming viral capsids to the nuclear periphery was unaffected by the cholesterol reduction, suggesting that cell cholesterol is important for the HSV-1 replicative cycle at a stage(s) beyond entry, after the arrival of capsids at the nucleus. The synthesis and release of infectious HSV-1 and cell-to-cell spread of infection were all impaired in cholesterol-reduced cells. Propagation of HSV-1 on DHCR24 Ϫ/Ϫ fibroblasts, which lack the desmosterol-to-cholesterol conversion enzyme, resulted in the generation of infectious extracellular virions (HSV des ) that lack cholesterol and likely contain desmosterol. The specific infectivities (PFU per viral genome) of HSV chol and HSV des were similar, suggesting cholesterol and desmosterol in the HSV envelope support similar levels of infectivity. However, infected DHCR24 Ϫ/Ϫ fibroblasts released ϳ1 log less infectious HSV des and ϳ1.5 log fewer particles than release of cholesterol-containing particles (HSV chol ) from parental fibroblasts, suggesting that the hydrocarbon tail of cholesterol facilitates viral synthesis. Together, the results suggest multiple roles for cholesterol in the HSV-1 replicative cycle.IMPORTANCE HSV-1 infections are associated with a wide range of clinical manifestations that are of public health importance. Cholesterol is a key player in the complex interaction between viral and cellular factors that allows HSV-1 to enter host cells and establish infection. Previous reports have demonstrated a role for cellular cholesterol in the entry of HSV-1 into target cells. Here, we employed both chemical treatment and cells that were genetically defined to synthesize only desmosterol to demonstrate that cholesterol is important at stages following the initial entry and transport of viral capsids to the nucleus. Viral protein expression, encapsidation of the viral genome, and the release of mature virions were impacted by the reduction of cellular cholesterol. Cholesterol was also critical for cell-to-cell spread of infection. These findings provide new insights into the cholesterol dependence of HSV-1 replication.KEYWORDS cholesterol, herpes simplex virus, herpesviruses, sterols T he entry of several herpesviruses into target cells requires cell membrane cholesterol (1-6). Membrane cholesterol is essential for maintaining membrane order, reducing permeability, and a host of other cellular functions, including cell signaling (7-10). Entry of the alphaherpesviruses herpes simplex virus 1 (HSV-1) and pseudorabies virus requires target membrane cholesterol at the fusion step (1, 3), but not for virus attachment to cells (2, 6). Herpesviruses utilize low-pH endosomal entry pathways and pH-independent routes, both of which require cholesterol (11-13). Membrane cholesterol plays a general role in viral entry...

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Cellular Cholesterol Facilitates the Postentry Replication Cycle of Herpes Simplex Virus 1

Wudiri

Nicola

2017

J Virol

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“…We also recently reported that RSV utilizes lipid rafts during virus budding (42), and since budding events of several viruses are regulated by Nedd proteins like Nedd4 (Nedd4 is a component of ESCRT [the endosomal sorting complex required for transport] pathway [43,44] that utilizes L (lateassembly) domains during virus budding), we knocked down (via RNA interference [RNAi]) several Nedd proteins, including Nedd4 and Nedd8 (as a control). During those studies, we surpris-ingly uncovered that Nedd8 knockdown drastically reduced IL-1␤ production from RSV-infected cells.…”

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Nedd8 Regulates Inflammasome-Dependent Caspase-1 Activation

Segovia

Tsai

Chang

et al. 2015

Molecular and Cellular Biology

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dCaspase-1 is activated by the inflammasome complex to process cytokines like interleukin-1␤ (IL-1␤). Pro-caspase-1 consists of three domains, CARD, p20, and p10. Association of pro-caspase-1 with the inflammasome results in initiation of its autocatalytic activity, culminating in self-cleavage that generates catalytically active subunits (p10 and p20). In the current study, we show that Nedd8 is required for efficient self-cleavage of pro-caspase-1 to generate its catalytically active subunits. Nedd8 silencing or treating cells with the neddylation inhibitor MLN4924 led to diminished caspase-1 processing and reduced IL-1␤ maturation following inflammasome activation. Coimmunoprecipitation and mass spectrometric analysis of 293 cells overexpressing procaspase-1 (and CARD) and Nedd8 suggested possible neddylation of caspase-1 CARD. Following inflammasome activation in primary macrophages, we observed colocalization of endogenous Nedd8 with caspase-1. Similarly, interaction of endogenous Nedd8 with caspase-1 CARD was detected in inflammasome-activated macrophages. Furthermore, enhanced autocatalytic activity of pro-caspase-1 was observed following Nedd8 overexpression in 293 cells, and such activity in inflammasome-activated macrophages was drastically diminished upon treatment of cells with MLN4924. Thus, our studies demonstrate a role of Nedd8 in regulating caspase-1 activation following inflammasome activation, presumably via augmenting autoprocessing/cleavage of pro-caspase-1 into its corresponding catalytically active subunits.

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“…3 Cholesterol, an essential component of the plasma membrane, has been implicated in the regulation of membrane fluidity, permeability, and cell surface receptor function. [4][5][6] Because cholesterol contributes to the establishment of a cornified barrier, it plays a crucial role in keratinocytes. Atopic dermatitis has even been shown to occur in parallel with keratinocytes disrupted by lipid rafts.…”

Section: Discussionmentioning

confidence: 99%

“…It is also an important contributor to cell-cell adhesion, migration, and even endocytosis. [4][5][6][7] However, despite increasing interest in the bronchial epithelium, the possible role of cholesterol in inflammation of the airway or the development of asthma has not been investigated. Among the numerous cytokines and chemokines released from human airways, interleukin-8 (IL-8) is a representative…”

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Effect of Cholesterol Depletion On Interleukin-8 Production in Human Respiratory Epithelial Cells

Kim

Hong

Lee

et al. 2013

Journal of Allergy and Clinical Immunology

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rate from their surroundings. Cholesterol, the most abundant lipid component of animal cell membranes, regulates membrane fluidity and plays a crucial role in the formation and stabilization of membrane microdomains. It is also an important contributor to cell-cell adhesion, migration, and even endocytosis. [4][5][6][7] However, despite increasing interest in the bronchial epithelium, the possible role of cholesterol in inflammation of the airway or the development of asthma has not been investigated. Among the numerous cytokines and chemokines released from human airways, interleukin-8 (IL-8) is a representative Original ArticleAllergy Asthma Immunol Res. 2013 November;5(6):402-408. http://dx.doi.org/10. 4168/aair.2013.5.6.402 pISSN 2092-7355 • eISSN 2092 Purpose: The lipid entities of cell membranes are components of the immune system and important mediators of inflammation. Despite increasing interest in the function of epithelial cells in inflammation, the role of cholesterol in this process has not been described. Here, we investigated the effect of cholesterol depletion on the inflammatory process in airway epithelial cells via the expression of interleukin (IL)-8 as a marker of inflammation. Methods: A 549 cells were treated with 0.5% methyl-β-cyclodextrin as a selective cholesterol extractor. The IL-8 level was assessed by enzyme-linked immunosorbent assay and reassessed after cholesterol repletion. Mitogen-activated protein kinase (MAPK) inhibitors were used to determine the upstream signaling pathway for IL-8 production in cholesterol-depleted cells. Results: We found a relationship between the amount of cholesterol in A 549 cells and inflammation of the airway. IL-8 production was increased in cholesterol-depleted A 549 cells and restored by cholesterol repletion. IL-8 production was decreased by pretreatment with the extracellular signal-regulated kinase (ERK) inhibitor U0126 but not with JNK inhibitor II or the p38 MAPK inhibitor SB202190. Conclusions: Our findings suggest that inflammatory responses are increased in cholesterol-depleted epithelial cells via the MAPK signaling system, predominantly by the ERK pathway. We conclude that the lipid components of airwayepithelial cells may play a role in the inflammatory process.

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Cholesterol-rich lipid rafts are required for release of infectious human respiratory syncytial virus particles

Cited by 54 publications

References 52 publications

Cellular Cholesterol Facilitates the Postentry Replication Cycle of Herpes Simplex Virus 1

Cellular Cholesterol Facilitates the Postentry Replication Cycle of Herpes Simplex Virus 1

Nedd8 Regulates Inflammasome-Dependent Caspase-1 Activation

Effect of Cholesterol Depletion On Interleukin-8 Production in Human Respiratory Epithelial Cells

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