Research Article: Host phosphatidic acid phosphatase lipin1 is rate limiting for functional hepatitis C virus replicase complex formation

Date Published: September 18, 2018

Publisher: Public Library of Science

Author(s): Lidia Mingorance, Victoria Castro, Ginés Ávila-Pérez, Gema Calvo, María Josefa Rodriguez, José L. Carrascosa, Sofía Pérez-del-Pulgar, Xavier Forns, Pablo Gastaminza, Aleem Siddiqui.

http://doi.org/10.1371/journal.ppat.1007284

Abstract

Hepatitis C virus (HCV) infection constitutes a significant health burden worldwide, because it is a major etiologic agent of chronic liver disease, cirrhosis and hepatocellular carcinoma. HCV replication cycle is closely tied to lipid metabolism and infection by this virus causes profound changes in host lipid homeostasis. We focused our attention on a phosphatidate phosphate (PAP) enzyme family (the lipin family), which mediate the conversion of phosphatidate to diacylglycerol in the cytoplasm, playing a key role in triglyceride biosynthesis and in phospholipid homeostasis. Lipins may also translocate to the nucleus to act as transcriptional regulators of genes involved in lipid metabolism. The best-characterized member of this family is lipin1, which cooperates with lipin2 to maintain glycerophospholipid homeostasis in the liver. Lipin1-deficient cell lines were generated by RNAi to study the role of this protein in different steps of HCV replication cycle. Using surrogate models that recapitulate different aspects of HCV infection, we concluded that lipin1 is rate limiting for the generation of functional replicase complexes, in a step downstream primary translation that leads to early HCV RNA replication. Infection studies in lipin1-deficient cells overexpressing wild type or phosphatase-defective lipin1 proteins suggest that lipin1 phosphatase activity is required to support HCV infection. Finally, ultrastructural and biochemical analyses in replication-independent models suggest that lipin1 may facilitate the generation of the membranous compartment that contains functional HCV replicase complexes.

Partial Text

Millions of humans are chronically infected by hepatitis C virus (HCV) worldwide [1]. Chronic HCV infection is a major biomedical problem as it causes liver inflammation and fibrosis, which can lead to severe liver disease, such as cirrhosis and hepatocellular carcinoma [2, 3]. There is no vaccine against HCV and, although blood-screening tests and other prophylactic measures have reduced the dissemination of this pathogen, a number of newly acquired infections still occur associated with risk behavior or with unknown origin [4, 5]. However, chronic HCV infection can be successfully eradicated from chronically infected individuals through specific direct-acting antiviral (DAA) combination therapies, virtually in all treated patients [6]. Since these specific treatments have only been in place recently, there are no sufficient clinical data on the long-term benefit of these treatments in relieving the severity of advanced liver disease [7, 8].

Hepatitis C virus replication cycle is tightly linked to host cell lipid metabolism and interference with cellular lipid homeostasis contributes to viral pathogenesis [3]. One of the most evident consequences of this interference is the high prevalence of liver steatosis among chronically infected patients [13, 60]. This clinical manifestation of the infection has been linked to, among others, chronic ER stress, mitochondrial dysfunction and metabolite depletion induced by HCV infection, which result in the activation of persistent homeostatic adaptation of the cellular lipid metabolism to permit cell survival, at the cost of pathogenic metabolic alterations [11, 61–64].

 

Source:

http://doi.org/10.1371/journal.ppat.1007284

 

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