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Increased long chain acyl-Coa synthetase activity and fatty acid import is linked to membrane synthesis for development of picornavirus replication organelles.

Nchoutmboube JA, Viktorova EG, Scott AJ, Ford LA, Pei Z, Watkins PA, Ernst RK, Belov GA - PLoS Pathog. (2013)

Bottom Line: Poliovirus protein 2A is required to trigger the activation of import of fatty acids independent of its protease activity.Shift in fatty acid import preferences by infected cells results in synthesis of phosphatidylcholines different from those in uninfected cells, arguing that the viral replication organelles possess unique properties compared to the pre-existing membranes.Our data show how poliovirus can change the overall cellular membrane homeostasis by targeting one critical process.

View Article: PubMed Central - PubMed

Affiliation: Virginia-Maryland Regional College of Veterinary Medicine, University of Maryland, College Park, Maryland, United States of America.

ABSTRACT
All positive strand (+RNA) viruses of eukaryotes replicate their genomes in association with membranes. The mechanisms of membrane remodeling in infected cells represent attractive targets for designing future therapeutics, but our understanding of this process is very limited. Elements of autophagy and/or the secretory pathway were proposed to be hijacked for building of picornavirus replication organelles. However, even closely related viruses differ significantly in their requirements for components of these pathways. We demonstrate here that infection with diverse picornaviruses rapidly activates import of long chain fatty acids. While in non-infected cells the imported fatty acids are channeled to lipid droplets, in infected cells the synthesis of neutral lipids is shut down and the fatty acids are utilized in highly up-regulated phosphatidylcholine synthesis. Thus the replication organelles are likely built from de novo synthesized membrane material, rather than from the remodeled pre-existing membranes. We show that activation of fatty acid import is linked to the up-regulation of cellular long chain acyl-CoA synthetase activity and identify the long chain acyl-CoA syntheatse3 (Acsl3) as a novel host factor required for polio replication. Poliovirus protein 2A is required to trigger the activation of import of fatty acids independent of its protease activity. Shift in fatty acid import preferences by infected cells results in synthesis of phosphatidylcholines different from those in uninfected cells, arguing that the viral replication organelles possess unique properties compared to the pre-existing membranes. Our data show how poliovirus can change the overall cellular membrane homeostasis by targeting one critical process. They explain earlier observations of increased phospholipid synthesis in infected cells and suggest a simple model of the structural development of the membranous scaffold of replication complexes of picorna-like viruses, that may be relevant for other (+)RNA viruses as well.

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Related in: MedlinePlus

A model of the structural development of picornavirus replication complexes based on activation of cellular acyl-CoA synthetase activity by viral proteins (2A is required, but is not sufficient in case of polio).Elevated acyl-CoA synthetase activity leads to increased import of fatty acids (FA) form the media and also to utilization of FA form intracellular sources (FAS- fatty acid synthase)resulting in upregulated synthesis of altered species of phosphatidylcholines (PC). PCs with short fatty acid moieties preferentially synthesized in polio-infected cells spontaneously assemble into characteristic tightly packed convoluted tubular membranes structures constituting structural scaffold of poliovirus replication organelles.
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ppat-1003401-g008: A model of the structural development of picornavirus replication complexes based on activation of cellular acyl-CoA synthetase activity by viral proteins (2A is required, but is not sufficient in case of polio).Elevated acyl-CoA synthetase activity leads to increased import of fatty acids (FA) form the media and also to utilization of FA form intracellular sources (FAS- fatty acid synthase)resulting in upregulated synthesis of altered species of phosphatidylcholines (PC). PCs with short fatty acid moieties preferentially synthesized in polio-infected cells spontaneously assemble into characteristic tightly packed convoluted tubular membranes structures constituting structural scaffold of poliovirus replication organelles.

Mentions: Our data provide a foundation for a simple model that may explain the structural development of the membranous replication organelles shared by at least picorna-like viruses (Fig. 8). Certainly many aspects of this model are hypothetical at this point and require further investigations to elucidate the mechanistic details. The elevated acyl-CoA synthetase activity in infected cells inevitably increases import of FAs from the extracellular media but also would activate FAs released from intracellular sources, thus allowing utilization of resources in different cell types or growth conditions. The resulting excess of long chain acyl-CoAs would stimulate further steps in phospholipid synthesis and result in continuous extrusion of new membranes. Moreover the preference of acyl-CoA synthetase activity in infected cells for shorter FAs would result in generating membranes with higher fluidity with the intrinsic propensity to assemble into tight tubular structures (myelin figures) [78] surprisingly similar to the picornavirus replication membranes [52], [53]. These new membranes would need to be decorated with the necessary viral and cellular factors to make them capable of supporting viral replication, but the generation of the structural scaffold seems to be a unique process activated in infected cells, independent of the elements of the secretory pathway or autophagy. The distinct properties of the FA metabolism in infected cells and the widespread reliance of diverse (+)RNA viruses on their activation represent an attractive target for development of future broad spectrum antiviral therapeutics.


Increased long chain acyl-Coa synthetase activity and fatty acid import is linked to membrane synthesis for development of picornavirus replication organelles.

Nchoutmboube JA, Viktorova EG, Scott AJ, Ford LA, Pei Z, Watkins PA, Ernst RK, Belov GA - PLoS Pathog. (2013)

A model of the structural development of picornavirus replication complexes based on activation of cellular acyl-CoA synthetase activity by viral proteins (2A is required, but is not sufficient in case of polio).Elevated acyl-CoA synthetase activity leads to increased import of fatty acids (FA) form the media and also to utilization of FA form intracellular sources (FAS- fatty acid synthase)resulting in upregulated synthesis of altered species of phosphatidylcholines (PC). PCs with short fatty acid moieties preferentially synthesized in polio-infected cells spontaneously assemble into characteristic tightly packed convoluted tubular membranes structures constituting structural scaffold of poliovirus replication organelles.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3675155&req=5

ppat-1003401-g008: A model of the structural development of picornavirus replication complexes based on activation of cellular acyl-CoA synthetase activity by viral proteins (2A is required, but is not sufficient in case of polio).Elevated acyl-CoA synthetase activity leads to increased import of fatty acids (FA) form the media and also to utilization of FA form intracellular sources (FAS- fatty acid synthase)resulting in upregulated synthesis of altered species of phosphatidylcholines (PC). PCs with short fatty acid moieties preferentially synthesized in polio-infected cells spontaneously assemble into characteristic tightly packed convoluted tubular membranes structures constituting structural scaffold of poliovirus replication organelles.
Mentions: Our data provide a foundation for a simple model that may explain the structural development of the membranous replication organelles shared by at least picorna-like viruses (Fig. 8). Certainly many aspects of this model are hypothetical at this point and require further investigations to elucidate the mechanistic details. The elevated acyl-CoA synthetase activity in infected cells inevitably increases import of FAs from the extracellular media but also would activate FAs released from intracellular sources, thus allowing utilization of resources in different cell types or growth conditions. The resulting excess of long chain acyl-CoAs would stimulate further steps in phospholipid synthesis and result in continuous extrusion of new membranes. Moreover the preference of acyl-CoA synthetase activity in infected cells for shorter FAs would result in generating membranes with higher fluidity with the intrinsic propensity to assemble into tight tubular structures (myelin figures) [78] surprisingly similar to the picornavirus replication membranes [52], [53]. These new membranes would need to be decorated with the necessary viral and cellular factors to make them capable of supporting viral replication, but the generation of the structural scaffold seems to be a unique process activated in infected cells, independent of the elements of the secretory pathway or autophagy. The distinct properties of the FA metabolism in infected cells and the widespread reliance of diverse (+)RNA viruses on their activation represent an attractive target for development of future broad spectrum antiviral therapeutics.

Bottom Line: Poliovirus protein 2A is required to trigger the activation of import of fatty acids independent of its protease activity.Shift in fatty acid import preferences by infected cells results in synthesis of phosphatidylcholines different from those in uninfected cells, arguing that the viral replication organelles possess unique properties compared to the pre-existing membranes.Our data show how poliovirus can change the overall cellular membrane homeostasis by targeting one critical process.

View Article: PubMed Central - PubMed

Affiliation: Virginia-Maryland Regional College of Veterinary Medicine, University of Maryland, College Park, Maryland, United States of America.

ABSTRACT
All positive strand (+RNA) viruses of eukaryotes replicate their genomes in association with membranes. The mechanisms of membrane remodeling in infected cells represent attractive targets for designing future therapeutics, but our understanding of this process is very limited. Elements of autophagy and/or the secretory pathway were proposed to be hijacked for building of picornavirus replication organelles. However, even closely related viruses differ significantly in their requirements for components of these pathways. We demonstrate here that infection with diverse picornaviruses rapidly activates import of long chain fatty acids. While in non-infected cells the imported fatty acids are channeled to lipid droplets, in infected cells the synthesis of neutral lipids is shut down and the fatty acids are utilized in highly up-regulated phosphatidylcholine synthesis. Thus the replication organelles are likely built from de novo synthesized membrane material, rather than from the remodeled pre-existing membranes. We show that activation of fatty acid import is linked to the up-regulation of cellular long chain acyl-CoA synthetase activity and identify the long chain acyl-CoA syntheatse3 (Acsl3) as a novel host factor required for polio replication. Poliovirus protein 2A is required to trigger the activation of import of fatty acids independent of its protease activity. Shift in fatty acid import preferences by infected cells results in synthesis of phosphatidylcholines different from those in uninfected cells, arguing that the viral replication organelles possess unique properties compared to the pre-existing membranes. Our data show how poliovirus can change the overall cellular membrane homeostasis by targeting one critical process. They explain earlier observations of increased phospholipid synthesis in infected cells and suggest a simple model of the structural development of the membranous scaffold of replication complexes of picorna-like viruses, that may be relevant for other (+)RNA viruses as well.

Show MeSH
Related in: MedlinePlus