title: The Hepatitis C Virus-induced NLRP3 Inflammasome Activates the Sterol Regulatory Element-binding Protein (SREBP) and Regulates Lipid Metabolism.
abstract: Hepatitis C virus (HCV) relies on host lipids and lipid droplets for replication and morphogenesis. The accumulation of lipid droplets in infected hepatocytes manifests as hepatosteatosis, a common pathology observed in chronic hepatitis C patients. One way by which HCV promotes the accumulation of intracellular lipids is through enhancing de novo lipogenesis by activating the sterol regulatory element-binding proteins (SREBPs). In general, activation of SREBPs occurs during cholesterol depletion. Interestingly, during HCV infection, the activation of SREBPs occurs under normal cholesterol levels, but the underlying mechanisms are still elusive. Our previous study has demonstrated the activation of the inflammasome complex in HCV-infected human hepatoma cells. In this study, we elucidate the potential link between chronic hepatitis C-associated inflammation and alteration of lipid homeostasis in infected cells. Our results reveal that the HCV-activated NLRP3 inflammasome is required for the up-regulation of lipogenic genes such as 3-hydroxy-3-methylglutaryl-coenzyme A synthase, fatty acid synthase, and stearoyl-CoA desaturase. Using pharmacological inhibitors and siRNA against the inflammasome components (NLRP3, apoptosis-associated speck-like protein containing a CARD, and caspase-1), we further show that the activation of the NLRP3 inflammasome plays a critical role in lipid droplet formation. NLRP3 inflammasome activation in HCV-infected cells enables caspase-1-mediated degradation of insulin-induced gene proteins. This subsequently leads to the transport of the SREBP cleavage-activating protein·SREBP complex from the endoplasmic reticulum to the Golgi, followed by proteolytic activation of SREBPs by S1P and S2P in the Golgi. Typically, inflammasome activation leads to viral clearance. Paradoxically, here we demonstrate how HCV exploits the NLRP3 inflammasome to activate SREBPs and host lipid metabolism, leading to liver disease pathogenesis associated with chronic HCV.
authors.affiliation: From the Department of Microbiology and Immunology, H. M. Bligh Cancer Research Laboratories, Rosalind Franklin University of Medicine and Science, Chicago Medical School, North Chicago, Illinois 60064 and.
authors.forename: Steven
authors.initials: S
authors.lastname: McRae
authors.affiliation: From the Department of Microbiology and Immunology, H. M. Bligh Cancer Research Laboratories, Rosalind Franklin University of Medicine and Science, Chicago Medical School, North Chicago, Illinois 60064 and.
authors.forename: Jawed
authors.initials: J
authors.lastname: Iqbal
authors.affiliation: From the Department of Microbiology and Immunology, H. M. Bligh Cancer Research Laboratories, Rosalind Franklin University of Medicine and Science, Chicago Medical School, North Chicago, Illinois 60064 and.
authors.forename: Mehuli
authors.initials: M
authors.lastname: Sarkar-Dutta
authors.affiliation: From the Department of Microbiology and Immunology, H. M. Bligh Cancer Research Laboratories, Rosalind Franklin University of Medicine and Science, Chicago Medical School, North Chicago, Illinois 60064 and.
authors.forename: Samantha
authors.initials: S
authors.lastname: Lane
authors.affiliation: From the Department of Microbiology and Immunology, H. M. Bligh Cancer Research Laboratories, Rosalind Franklin University of Medicine and Science, Chicago Medical School, North Chicago, Illinois 60064 and.
authors.forename: Abhiram
authors.initials: A
authors.lastname: Nagaraj
authors.affiliation: the Department of Medicine, Section of Digestive Diseases and Nutrition, University of Oklahoma, Oklahoma City, Oklahoma 73104.
authors.forename: Naushad
authors.initials: N
authors.lastname: Ali
authors.affiliation: From the Department of Microbiology and Immunology, H. M. Bligh Cancer Research Laboratories, Rosalind Franklin University of Medicine and Science, Chicago Medical School, North Chicago, Illinois 60064 and gulam.waris@rosalindfranklin.edu.
authors.forename: Gulam
authors.initials: G
authors.lastname: Waris
mesh_terms: D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010450:Endopeptidases / Q000737:chemistry / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology; D016174:Hepacivirus / Q000187:drug effects / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000821:virology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D058847:Inflammasomes / Q000187:drug effects / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D050155:Lipogenesis / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology; D043484:Proprotein Convertases / Q000737:chemistry / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D034622:RNA Interference; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000819:agonists* / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000819:agonists* / Q000378:metabolism
chemical_list: D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D015853:Cysteine Proteinase Inhibitors; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C402202:PYCARD protein, human; C497387:SREBF1 protein, human; C497390:SREBF2 protein, human; C102196:SREBP cleavage-activating protein; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D010450:Endopeptidases; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C115575:membrane-bound transcription factor peptidase, site 1; D020170:Caspase 1; C112686:SREBP site 2 protease
keywords: NLRP3 inflammasome; SREBP; hepatitis virus; inflammasome; inflammation; lipid metabolism; liver injury