Exocytosis of Alphaherpesvirus Virions, Light Particles, and Glycoproteins Uses Constitutive Secretory Mechanisms

Hogue, Ian B.; Scherer, Julian; Enquist, Lynn W.

doi:10.1128/mbio.00820-16

Cited by 52 publications

(76 citation statements)

References 41 publications

(65 reference statements)

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“…6B). HSV-1 commandeers the cellular exocytic machinery for the release of mature virus (46)(47)(48)(49). The role of cholesterol in the release and spread of HSV-1 might be explained partly by cholesterol-dependent vesicular exocytosis (50,51).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

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

Wudiri

Nicola

2017

J Virol

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“…Organelles are also necessary for the trafficking of viral proteins to sites of virion maturation (Checkley et al., 2011), as well as for the formation of these virus assembly sites (Alwine, 2012). Upon virion maturation, organelle components facilitate transport and release of the viral progeny (Hogue et al, 2016). Given their dependence on organelle functions, viruses need to actively modulate organelle dynamics throughout the progression of infection either by regulating host protein expression or by targeting viral proteins to specific organelles.…”

Section: Introductionmentioning

confidence: 99%

A Portrait of the Human Organelle Proteome In Space and Time during Cytomegalovirus Infection

2016

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SUMMARY The organelles within a eukaryotic host are manipulated by viruses to support successful virus replication and spread of infection, yet the global impact of viral infection on host organelles is poorly understood. Integrating microscopy, sub-cellular fractionation, mass spectrometry, and functional analyses, we conducted a cell-wide study of organelles in primary fibroblasts throughout the timecourse of human cytomegalovirus (HCMV) infection. We used label-free and isobaric-labeling proteomics to characterize nearly 4,000 host and 100 viral proteins, then classified their specific subcellular locations over time using machine learning. We observed a global reorganization of proteins across the secretory pathway, plasma membrane, and mitochondria, including reorganization and processing of lysosomal proteins into distinct subpopulations and translocations of individual proteins between organelles at specific timepoints. We also demonstrate that MYO18A, an unconventional myosin that translocates from the plasma membrane to the viral assembly complex, is necessary for efficient HCMV replication. This study provides a comprehensive resource for understanding host and virus biology during HCMV pathogenesis.

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“…Alpha herpesviruses include important pathogens, such as HSV-1, HSV-2, and VZV (Hogue et al, 2016). Increasing lines of evidence indicate that alpha herpesviruses utilize exosomes to deliver cargo such as transcripts (mRNAs, miRNAs, and DNA) and proteins.…”

Section: Exosomes In Alpha Herpesvirus Infectionmentioning

confidence: 99%

Extracellular vesicles: novel vehicles in herpesvirus infection

et al. 2017

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Herpesviruses are remarkable pathogens that have evolved multiple mechanisms to evade host immunity, ensuring their proliferation and egress. Among these mechanisms, herpesviruses utilize elaborate extracellular vesicles, including exosomes, for the intricate interplay between infected host and recipient cells. Herpesviruses incorporate genome expression products and direct cellular products into exosomal cargoes. These components alter the content and function of exosomes released from donor cells, thus affecting the downstream signalings of recipient cells. In this way, herpesviruses hijack exosomal pathways to ensure their survival and persistence, and exosomes are emerging as critical mediators for virus infection-associated intercellular communication and microenvironment alteration. In this review, the function and effects of exosomes in herpesvirus infection will be discussed, so that we will have a better understanding about the pathogenesis of herpesviruses.

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Exocytosis of Alphaherpesvirus Virions, Light Particles, and Glycoproteins Uses Constitutive Secretory Mechanisms

Cited by 52 publications

References 41 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

A Portrait of the Human Organelle Proteome In Space and Time during Cytomegalovirus Infection

Extracellular vesicles: novel vehicles in herpesvirus infection

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