TY - JOUR
T1 - Ebola virus requires phosphatidylinositol (3,5) bisphosphate production for efficient viral entry
AU - Qiu, Shirley
AU - Leung, Anders
AU - Bo, Yuxia
AU - Kozak, Robert A.
AU - Anand, Sai Priya
AU - Warkentin, Corina
AU - Salambanga, Fabiola D.R.
AU - Cui, Jennifer
AU - Kobinger, Gary
AU - Kobasa, Darwyn
AU - Côté, Marceline
N1 - Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2018/1/1
Y1 - 2018/1/1
N2 - For entry, Ebola virus (EBOV) requires the interaction of its viral glycoprotein with the cellular protein Niemann-Pick C1 (NPC1) which resides in late endosomes and lysosomes. How EBOV is trafficked and delivered to NPC1 and whether this is positively regulated during entry remain unclear. Here, we show that the PIKfyve-ArPIKfyve-Sac3 cellular complex, which is involved in the metabolism of phosphatidylinositol (3,5) bisphosphate (PtdIns(3,5)P2), is critical for EBOV infection. Although the expression of all subunits of the complex was required for efficient entry, PIKfyve kinase activity was specifically critical for entry by all pathogenic filoviruses. Inhibition of PIKfyve prevented colocalization of EBOV with NPC1 and led to virus accumulation in intracellular vesicles with characteristics of early endosomes. Importantly, genetically-encoded phosphoinositide probes revealed an increase in PtdIns(3,5)P2-positive vesicles in cells during EBOV entry. Taken together, our studies suggest that EBOV requires PtdIns(3,5)P2 production in cells to promote efficient delivery to NPC1.
AB - For entry, Ebola virus (EBOV) requires the interaction of its viral glycoprotein with the cellular protein Niemann-Pick C1 (NPC1) which resides in late endosomes and lysosomes. How EBOV is trafficked and delivered to NPC1 and whether this is positively regulated during entry remain unclear. Here, we show that the PIKfyve-ArPIKfyve-Sac3 cellular complex, which is involved in the metabolism of phosphatidylinositol (3,5) bisphosphate (PtdIns(3,5)P2), is critical for EBOV infection. Although the expression of all subunits of the complex was required for efficient entry, PIKfyve kinase activity was specifically critical for entry by all pathogenic filoviruses. Inhibition of PIKfyve prevented colocalization of EBOV with NPC1 and led to virus accumulation in intracellular vesicles with characteristics of early endosomes. Importantly, genetically-encoded phosphoinositide probes revealed an increase in PtdIns(3,5)P2-positive vesicles in cells during EBOV entry. Taken together, our studies suggest that EBOV requires PtdIns(3,5)P2 production in cells to promote efficient delivery to NPC1.
KW - Filoviruses
KW - Vesicular trafficking
KW - Viral entry
KW - Virus-cell interactions
UR - http://www.scopus.com/inward/record.url?scp=85030852346&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85030852346&partnerID=8YFLogxK
U2 - 10.1016/j.virol.2017.09.028
DO - 10.1016/j.virol.2017.09.028
M3 - Article
C2 - 29031163
AN - SCOPUS:85030852346
SN - 0042-6822
VL - 513
SP - 17
EP - 28
JO - Virology
JF - Virology
ER -