Abstract
ABSTRACTThe release of infectious hepatitis C virus (HCV) particles from infected cells remains poorly characterized. We previously demonstrated that virus release is dependent on the endosomal sorting complex required for transport (ESCRT). Here, we show a critical role of trans-Golgi network (TGN)-endosome trafficking during the assembly, but principally the secretion, of infectious virus. This was demonstrated by both small interfering RNA (siRNA)-mediated silencing of TGN-associated adaptor proteins and a panel of dominant negative (DN) Rab GTPases involved in TGN-endosome trafficking steps. Importantly, interfering with factors critical for HCV release did not have a concomitant effect on secretion of triglycerides, ApoB, or ApoE, indicating that particles are likely released from Huh7 cells via pathways distinct from that of very-low-density lipoprotein (VLDL). Finally, we show that HCV NS2 perturbs TGN architecture, redistributing TGN membranes to closely associate with HCV core protein residing on lipid droplets. These findings support the notion that HCV hijacks TGN-endosome trafficking to facilitate particle assembly and release. Moreover, although essential for assembly and infectivity, the trafficking of mature virions is seemingly independent of host lipoproteins.IMPORTANCE The mechanisms by which infectious hepatitis C virus particles are assembled and released from the cell are poorly understood. We show that the virus subverts host cell trafficking pathways to effect the release of virus particles and disrupts the structure of the Golgi apparatus, a key cellular organelle involved in secretion. In addition, we demonstrate that the mechanisms used by the virus to exit the cell are distinct from those used by the cell to release lipoproteins, suggesting that the virus effects a unique modification to cellular trafficking pathways.
Highlights
The release of infectious hepatitis C virus (HCV) particles from infected cells remains poorly characterized
Of infectious intracellular HCV virions occurs in close proximity to lipid droplets (LDs) and is dependent on factors required during very-low-density lipoprotein (VLDL) assembly, including DGAT1 [13], apolipoprotein B-100 (ApoB) [14], and ApoE [15]
Huh7 cells transfected with an small interfering RNA (siRNA) were subsequently infected either with JFH-1 to assess infectious particle production or with a luciferaseexpressing J6/JFH-1 chimeric virus (J6/JFH-1luc) to measure genome replication
Summary
The release of infectious hepatitis C virus (HCV) particles from infected cells remains poorly characterized. We show a critical role of trans-Golgi network (TGN)-endosome trafficking during the assembly, but principally the secretion, of infectious virus. This was demonstrated by both small interfering RNA (siRNA)-mediated silencing of TGN-associated adaptor proteins and a panel of dominant negative (DN) Rab GTPases involved in TGN-endosome trafficking steps. We show that HCV NS2 perturbs TGN architecture, redistributing TGN membranes to closely associate with HCV core protein residing on lipid droplets These findings support the notion that HCV hijacks TGN-endosome trafficking to facilitate particle assembly and release. Of infectious intracellular HCV virions occurs in close proximity to LDs and is dependent on factors required during very-low-density lipoprotein (VLDL) assembly, including DGAT1 [13], apolipoprotein B-100 (ApoB) [14], and ApoE [15]. We, along with others, demonstrated that HCV release is dependent on components of the endosomal sorting complex required
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
