Abstract
Rapid development of complex membranous replication structures is a hallmark of picornavirus infections. However, neither the mechanisms underlying such dramatic reorganization of the cellular membrane architecture, nor the specific role of these membranes in the viral life cycle are sufficiently understood. Here we demonstrate that the cellular enzyme CCTα, responsible for the rate-limiting step in phosphatidylcholine synthesis, translocates from the nuclei to the cytoplasm upon infection and associates with the replication membranes, resulting in the rerouting of lipid synthesis from predominantly neutral lipids to phospholipids. The bulk supply of long chain fatty acids necessary to support the activated phospholipid synthesis in infected cells is provided by the hydrolysis of neutral lipids stored in lipid droplets. Such activation of phospholipid synthesis drives the massive membrane remodeling in infected cells. We also show that complex membranous scaffold of replication organelles is not essential for viral RNA replication but is required for protection of virus propagation from the cellular anti-viral response, especially during multi-cycle replication conditions. Inhibition of infection-specific phospholipid synthesis provides a new paradigm for controlling infection not by suppressing viral replication but by making it more visible to the immune system.
Highlights
The positive strand RNA ((+)RNA) viruses of eukaryotes universally assemble their RNA replication machinery in association with specialized membranous domains, featuring unique lipid and protein composition [1,2,3]
The cellular pathways hijacked to support viral replication may provide a promising class of targets for anti-viral therapeutics, which will be effective against broad groups of viruses relying on the same cellular pathways, and will likely be refractory to the development of resistance since cellular factors are not subject to selection
All (+)RNA viruses share the requirement for cellular membranes to assemble replication complexes
Summary
The positive strand RNA ((+)RNA) viruses of eukaryotes universally assemble their RNA replication machinery in association with specialized membranous domains, featuring unique lipid and protein composition [1,2,3]. It is hypothesized that membranes may facilitate replication by increasing local concentration of the viral proteins, providing a scaffold for assembly of the multi-subunit replication complexes, and/or by hiding the dsRNA replication intermediates from cellular sensors of infection [4]. In spite of the central role of the membranous replication organelles in the life cycle of (+)RNA viruses, our knowledge about the mechanistic details of their formation in most viral systems is very limited, and the experimental evidence supporting their importance for specific replication steps is scarce. Picornavidae is a family of small non-enveloped (+)RNA viruses of vertebrate hosts, and the number and diversity of known picornaviruses is rapidly increasing. Proteins encoded in the P2-P3 region of the viral genome as well as the corresponding cleavage intermediates are responsible for genome replication, while the P1 region codes for capsid proteins
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