Human subtilase SKI-1/S1P is a master regulator of the HCV Lifecycle and a potential host cell target for developing indirect-acting antiviral agents
(2012) In PLoS Pathogens 8(1).- Abstract
HCV infection is a major risk factor for liver cancer and liver transplantation worldwide. Overstimulation of host lipid metabolism in the liver by HCV-encoded proteins during viral infection creates a favorable environment for virus propagation and pathogenesis. In this study, we hypothesize that targeting cellular enzymes acting as master regulators of lipid homeostasis could represent a powerful approach to developing a novel class of broad-spectrum antivirals against infection associated with human Flaviviridae viruses such as hepatitis C virus (HCV), whose assembly and pathogenesis depend on interaction with lipid droplets (LDs). One such master regulator of cholesterol metabolic pathways is the host subtilisin/kexin-isozyme-1... (More)
HCV infection is a major risk factor for liver cancer and liver transplantation worldwide. Overstimulation of host lipid metabolism in the liver by HCV-encoded proteins during viral infection creates a favorable environment for virus propagation and pathogenesis. In this study, we hypothesize that targeting cellular enzymes acting as master regulators of lipid homeostasis could represent a powerful approach to developing a novel class of broad-spectrum antivirals against infection associated with human Flaviviridae viruses such as hepatitis C virus (HCV), whose assembly and pathogenesis depend on interaction with lipid droplets (LDs). One such master regulator of cholesterol metabolic pathways is the host subtilisin/kexin-isozyme-1 (SKI-1)--or site-1 protease (S1P). SKI-1/S1P plays a critical role in the proteolytic activation of sterol regulatory element binding proteins (SREBPs), which control expression of the key enzymes of cholesterol and fatty-acid biosynthesis. Here we report the development of a SKI-1/S1P-specific protein-based inhibitor and its application to blocking the SREBP signaling cascade. We demonstrate that SKI-1/S1P inhibition effectively blocks HCV from establishing infection in hepatoma cells. The inhibitory mechanism is associated with a dramatic reduction in the abundance of neutral lipids, LDs, and the LD marker: adipose differentiation-related protein (ADRP)/perilipin 2. Reduction of LD formation inhibits virus assembly from infected cells. Importantly, we confirm that SKI-1/S1P is a key host factor for HCV infection by using a specific active, site-directed, small-molecule inhibitor of SKI-1/S1P: PF-429242. Our studies identify SKI-1/S1P as both a novel regulator of the HCV lifecycle and as a potential host-directed therapeutic target against HCV infection and liver steatosis. With identification of an increasing number of human viruses that use host LDs for infection, our results suggest that SKI-1/S1P inhibitors may allow development of novel broad-spectrum biopharmaceuticals that could lead to novel indirect-acting antiviral options with the current standard of care.
(Less)
- author
- Olmstead, Andrea D ; Knecht, Wolfgang LU ; Lazarov, Ina ; Dixit, Surjit B and Jean, François
- publishing date
- 2012-01
- type
- Contribution to journal
- publication status
- published
- keywords
- Antiviral Agents/pharmacology, Cell Line, Tumor, Cholesterol/biosynthesis, Drug Design, Fatty Acids/biosynthesis, Fatty Liver/drug therapy, Hepacivirus/physiology, Hepatitis C/drug therapy, Humans, Membrane Proteins/genetics, Perilipin-2, Proprotein Convertases/antagonists & inhibitors, Protease Inhibitors/pharmacology, Proteolysis/drug effects, Serine Endopeptidases/genetics, Sterol Regulatory Element Binding Proteins/genetics, Virus Assembly/drug effects
- in
- PLoS Pathogens
- volume
- 8
- issue
- 1
- article number
- e1002468
- publisher
- Public Library of Science (PLoS)
- external identifiers
-
- scopus:84857468652
- pmid:22241994
- ISSN
- 1553-7374
- DOI
- 10.1371/journal.ppat.1002468
- language
- English
- LU publication?
- no
- id
- ab6d5117-2858-4142-b59b-8c74ec3634a2
- date added to LUP
- 2020-07-17 14:11:14
- date last changed
- 2024-04-03 11:48:13
@article{ab6d5117-2858-4142-b59b-8c74ec3634a2,
abstract = {{<p>HCV infection is a major risk factor for liver cancer and liver transplantation worldwide. Overstimulation of host lipid metabolism in the liver by HCV-encoded proteins during viral infection creates a favorable environment for virus propagation and pathogenesis. In this study, we hypothesize that targeting cellular enzymes acting as master regulators of lipid homeostasis could represent a powerful approach to developing a novel class of broad-spectrum antivirals against infection associated with human Flaviviridae viruses such as hepatitis C virus (HCV), whose assembly and pathogenesis depend on interaction with lipid droplets (LDs). One such master regulator of cholesterol metabolic pathways is the host subtilisin/kexin-isozyme-1 (SKI-1)--or site-1 protease (S1P). SKI-1/S1P plays a critical role in the proteolytic activation of sterol regulatory element binding proteins (SREBPs), which control expression of the key enzymes of cholesterol and fatty-acid biosynthesis. Here we report the development of a SKI-1/S1P-specific protein-based inhibitor and its application to blocking the SREBP signaling cascade. We demonstrate that SKI-1/S1P inhibition effectively blocks HCV from establishing infection in hepatoma cells. The inhibitory mechanism is associated with a dramatic reduction in the abundance of neutral lipids, LDs, and the LD marker: adipose differentiation-related protein (ADRP)/perilipin 2. Reduction of LD formation inhibits virus assembly from infected cells. Importantly, we confirm that SKI-1/S1P is a key host factor for HCV infection by using a specific active, site-directed, small-molecule inhibitor of SKI-1/S1P: PF-429242. Our studies identify SKI-1/S1P as both a novel regulator of the HCV lifecycle and as a potential host-directed therapeutic target against HCV infection and liver steatosis. With identification of an increasing number of human viruses that use host LDs for infection, our results suggest that SKI-1/S1P inhibitors may allow development of novel broad-spectrum biopharmaceuticals that could lead to novel indirect-acting antiviral options with the current standard of care.</p>}},
author = {{Olmstead, Andrea D and Knecht, Wolfgang and Lazarov, Ina and Dixit, Surjit B and Jean, François}},
issn = {{1553-7374}},
keywords = {{Antiviral Agents/pharmacology; Cell Line, Tumor; Cholesterol/biosynthesis; Drug Design; Fatty Acids/biosynthesis; Fatty Liver/drug therapy; Hepacivirus/physiology; Hepatitis C/drug therapy; Humans; Membrane Proteins/genetics; Perilipin-2; Proprotein Convertases/antagonists & inhibitors; Protease Inhibitors/pharmacology; Proteolysis/drug effects; Serine Endopeptidases/genetics; Sterol Regulatory Element Binding Proteins/genetics; Virus Assembly/drug effects}},
language = {{eng}},
number = {{1}},
publisher = {{Public Library of Science (PLoS)}},
series = {{PLoS Pathogens}},
title = {{Human subtilase SKI-1/S1P is a master regulator of the HCV Lifecycle and a potential host cell target for developing indirect-acting antiviral agents}},
url = {{http://dx.doi.org/10.1371/journal.ppat.1002468}},
doi = {{10.1371/journal.ppat.1002468}},
volume = {{8}},
year = {{2012}},
}