Cell death-inducing DFFA-like effector b is required for hepatitis C virus entry into hepatocytes.
The molecular mechanism of the hepatic tropism of hepatitis C virus (HCV) remains incompletely defined. In vitro hepatic differentiation of pluripotent stem cells produces hepatocyte-like cells (HLCs) permissive for HCV infection, providing an opportunity for studying liver development and host determinants of HCV susceptibility. We previously identified the transition stage of HCV permissiveness and now investigate whether a host protein whose expression is induced during this transition stage is important for HCV infection. We suppressed the expression of a liver-specific protein, cell death-inducing DFFA-like effector b (CIDEB), and performed hepatocyte function and HCV infection assays. We also used a variety of cell-based assays to dissect the specific step of the HCV life cycle that potentially requires CIDEB function. We found CIDEB to be an essential cofactor for HCV entry into hepatocytes. Genetic interference with CIDEB in stem cells followed by hepatic differentiation leads to HLCs that are refractory to HCV infection, and infection time course experiments revealed that CIDEB functions in a late step of HCV entry, possibly to facilitate membrane fusion. The role of CIDEB in mediating HCV entry is distinct from those of the well-established receptors, as it is not required for HCV pseudoparticle entry. Finally, HCV infection effectively downregulates CIDEB protein through a posttranscriptional mechanism.


OBJECTIVE
This study identifies a hepatitis C virus (HCV) entry cofactor that is required for HCV infection of hepatocytes and potentially facilitates membrane fusion between viral and host membranes. CIDEB and its interaction with HCV may open up new avenues of investigation of lipid droplets and viral entry.
Department of Biological Science, Florida State University, Tallahassee, Florida, USA.
Xianfang
X
Wu
Department of Biological Science, Florida State University, Tallahassee, Florida, USA.
Emily M
EM
Lee
Department of Biological Science, Florida State University, Tallahassee, Florida, USA.
Christy
C
Hammack
Department of Biological Science, Florida State University, Tallahassee, Florida, USA.
Jason M
JM
Robotham
Department of Biology, Georgia State University, Atlanta, Georgia, USA.
Mausumi
M
Basu
Department of Biological Science, Florida State University, Tallahassee, Florida, USA.
Jianshe
J
Lang
Department of Biology, Georgia State University, Atlanta, Georgia, USA.
Margo A
MA
Brinton
Department of Biological Science, Florida State University, Tallahassee, Florida, USA tang@bio.fsu.edu.
Hengli
H
Tang
D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D055785:Gene Knockdown Techniques; D016174:Hepacivirus / Q000502:physiology*; D022781:Hepatocytes / Q000821:virology*; D054884:Host-Pathogen Interactions; D006801:Humans; D053586:Virus Internalization
D051017:Apoptosis Regulatory Proteins; C112511:CIDEB protein, human