Endosomal egress and intercellular transmission of hepatic ApoE-containing lipoproteins and its exploitation by the hepatitis C virus

Liver-generated plasma Apolipoprotein E (ApoE)-containing lipoproteins (LPs) (ApoE-LPs) play central roles in lipid transport and metabolism. Perturbations of ApoE can result in several metabolic disorders and ApoE genotypes have been associated with multiple diseases. ApoE is synthesized at the end...

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Published in:	PLoS pathogens 2023-07, Vol.19 (7), p.e1011052-e1011052
Main Authors:	Pham, Minh-Tu, Lee, Ji-Young, Ritter, Christian, Thielemann, Roman, Meyer, Janis, Haselmann, Uta, Funaya, Charlotta, Laketa, Vibor, Rohr, Karl, Bartenschlager, Ralf
Format:	Article
Language:	eng
Subjects:	Apolipoprotein E Apolipoproteins Apolipoproteins E - metabolism Biology and Life Sciences Blood lipids Blood lipoproteins Care and treatment CD63 antigen Cell interactions Coronaviruses COVID-19 Diagnosis Egress Endoplasmic reticulum Endosomes Endosomes - metabolism Exploitation Fluorescence Genotypes Golgi apparatus Health aspects Hepacivirus - physiology Heparan sulfate Hepatitis Hepatitis C Hepatitis C virus Hepatocytes Homeostasis Humans Kinases Lipid metabolism Lipids Lipopolysaccharides - metabolism Lipoproteins Liver Liver cells Liver diseases Medicine and Health Sciences Metabolic disorders Metabolism Perturbation Physiological aspects Plasma Proteins Proteolipids Replicase Research and Analysis Methods Synthesis Triglycerides Vesicles Virus Assembly - physiology Virus diseases Viruses
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Summary:	Liver-generated plasma Apolipoprotein E (ApoE)-containing lipoproteins (LPs) (ApoE-LPs) play central roles in lipid transport and metabolism. Perturbations of ApoE can result in several metabolic disorders and ApoE genotypes have been associated with multiple diseases. ApoE is synthesized at the endoplasmic reticulum and transported to the Golgi apparatus for LP assembly; however, the ApoE-LPs transport pathway from there to the plasma membrane is largely unknown. Here, we established an integrative imaging approach based on a fully functional fluorescently tagged ApoE. We found that newly synthesized ApoE-LPs accumulate in CD63-positive endosomes of hepatocytes. In addition, we observed the co-egress of ApoE-LPs and CD63-positive intraluminal vesicles (ILVs), which are precursors of extracellular vesicles (EVs), along the late endosomal trafficking route in a microtubule-dependent manner. A fraction of ApoE-LPs associated with CD63-positive EVs appears to be co-transmitted from cell to cell. Given the important role of ApoE in viral infections, we employed as well-studied model the hepatitis C virus (HCV) and found that the viral replicase component nonstructural protein 5A (NS5A) is enriched in ApoE-containing ILVs. Interaction between NS5A and ApoE is required for the efficient release of ILVs containing HCV RNA. These vesicles are transported along the endosomal ApoE egress pathway. Taken together, our data argue for endosomal egress and transmission of hepatic ApoE-LPs, a pathway that is hijacked by HCV. Given the more general role of EV-mediated cell-to-cell communication, these insights provide new starting points for research into the pathophysiology of ApoE-related metabolic and infection-related disorders.
ISSN:	1553-7374 1553-7366 1553-7374