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.
Department of Biological Sciences, Rutgers University, Newark, NJ 07102, USA.
Nai-Yun
NY
Hsu
Olha
O
Ilnytska
Georgiy
G
Belov
Marianita
M
Santiana
Ying-Han
YH
Chen
Peter M
PM
Takvorian
Cyrilla
C
Pau
Hilde
H
van der Schaar
Neerja
N
Kaushik-Basu
Tamas
T
Balla
Craig E
CE
Cameron
Ellie
E
Ehrenfeld
Frank J M
FJ
van Kuppeveld
Nihal
N
Altan-Bonnet
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