Viral reorganization of the secretory pathway generates distinct organelles for RNA replication.
Many RNA viruses remodel intracellular membranes to generate specialized sites for RNA replication. How membranes are remodeled and what properties make them conducive for replication are unknown. Here we show how RNA viruses can manipulate multiple components of the cellular secretory pathway to generate organelles specialized for replication that are distinct in protein and lipid composition from the host cell. Specific viral proteins modulate effector recruitment by Arf1 GTPase and its guanine nucleotide exchange factor GBF1, promoting preferential recruitment of phosphatidylinositol-4-kinase IIIbeta (PI4KIIIbeta) to membranes over coat proteins, yielding uncoated phosphatidylinositol-4-phosphate (PI4P) lipid-enriched organelles. The PI4P-rich lipid microenvironment is essential for both enteroviral and flaviviral RNA replication; PI4KIIIbeta inhibition interferes with this process; and enteroviral RNA polymerases specifically bind PI4P. These findings reveal how RNA viruses can selectively exploit specific elements of the host to form specialized organelles where cellular phosphoinositide lipids are key to regulating viral RNA replication.
Hsu
Nai-Yun
NY
Department of Biological Sciences, Rutgers University, Newark, NJ 07102, USA.
Ilnytska
Olha
O
Belov
Georgiy
G
Santiana
Marianita
M
Chen
Ying-Han
YH
Takvorian
Peter M
PM
Pau
Cyrilla
C
van der Schaar
Hilde
H
Kaushik-Basu
Neerja
N
Balla
Tamas
T
Cameron
Craig E
CE
Ehrenfeld
Ellie
E
van Kuppeveld
Frank J M
FJ
Altan-Bonnet
Nihal
N
D004721:Endoplasmic Reticulum / Q000378:metabolism; D004770:Enterovirus / Q000378:metabolism*; D005416:Flavivirus / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism*; D055571:Secretory Pathway; D014779:Virus Replication
D018129:Phosphatidylinositol Phosphates; D012367:RNA, Viral