Hepatitis C Virus Infection and Intrinsic Disorder in the Signaling Pathways Induced by Toll-Like Receptors.

Abstract

Simple SummaryHuman hepatitis C virus causes contagious liver disease hepatitis C, which is broadly spread around the globe. Infection with this virus causes an inflammation of the liver that leads to both acute and chronic hepatitis, which, if left untreated, often results in the development of serious lifelong illnesses such as liver fibrosis, liver cirrhosis, hepatocellular carcinoma, and end-stage liver disease in humans. Toll-like receptors are a class of pattern recognition receptors that exist in liver parenchymal cells and various immune cells, and play an important role in the liver immune system by initiating multiple cellular downstream pathways in response to the recognition of pathogens such as hepatitis C virus. Proteins from the hepatitis C virus, Toll-like receptors themselves, and proteins from the pathways they activate are multifunctional. Since protein multifunctionality is commonly associated with intrinsic disorder (i.e., lack of stable 3D structures), we used an intrinsic disorder angle to examine the interplay between the hepatitis C virus infection and signaling pathways induced by Toll-like receptors. We show that almost all of these proteins contained noticeable levels of disorder, indicating that intrinsic disorder is prominently utilized in virus–host warfare.In this study, we examined the interplay between protein intrinsic disorder, hepatitis C virus (HCV) infection, and signaling pathways induced by Toll-like receptors (TLRs). To this end, 10 HCV proteins, 10 human TLRs, and 41 proteins from the TLR-induced downstream pathways were considered from the prevalence of intrinsic disorder. Mapping of the intrinsic disorder to the HCV-TLR interactome and to the TLR-based pathways of human innate immune response to the HCV infection demonstrates that substantial levels of intrinsic disorder are characteristic for proteins involved in the regulation and execution of these innate immunity pathways and in HCV-TLR interaction. Disordered regions, being commonly enriched in sites of various posttranslational modifications, may play important functional roles by promoting protein–protein interactions and support the binding of the analyzed proteins to other partners such as nucleic acids. It seems that this system represents an important illustration of the role of intrinsic disorder in virus–host warfare.