Temporal Proteome and Lipidome Profiles Reveal Hepatitis C Virus-Associated Reprogramming of Hepatocellular Metabolism and Bioenergetics

PLoS Pathogens

Jason E. McDermott¹  Katrina M. Waters¹  Sean C. Proll²  Michael G. Katze²  Deborah L. Diamond²  Kathie-Anne Walters²  Jon M. Jacobs³  Rui Zhao³  Christina M. Sorensen³  Qibin Zhang³  Marina A. Gritsenko³  Thomas O. Metz³  David G. Camp II³  Richard D. Smith³  Andrew J. Syder⁴  Charles M. Rice⁴ 

[1] Computational Biology & Bioinformatics, Pacific Northwest National Laboratory, Richland, Washington, United States of America;Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington, United States of America;Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, Washington, United States of America;Laboratory of Virology & Infectious Disease, Center for the Study of Hepatitis C, Rockefeller University, New York, New York, United States of America

关键词: Lipids;    Protein metabolism;    Fatty acids;    Cell metabolism;    Lipid analysis;    Protein abundance;    Drug metabolism;    Lipid metabolism;   

DOI  :  10.1371/journal.ppat.1000719

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Proteomic and lipidomic profiling was performed over a time course of acute hepatitis C virus (HCV) infection in cultured Huh-7.5 cells to gain new insights into the intracellular processes influenced by this virus. Our proteomic data suggest that HCV induces early perturbations in glycolysis, the pentose phosphate pathway, and the citric acid cycle, which favor host biosynthetic activities supporting viral replication and propagation. This is followed by a compensatory shift in metabolism aimed at maintaining energy homeostasis and cell viability during elevated viral replication and increasing cellular stress. Complementary lipidomic analyses identified numerous temporal perturbations in select lipid species (e.g. phospholipids and sphingomyelins) predicted to play important roles in viral replication and downstream assembly and secretion events. The elevation of lipotoxic ceramide species suggests a potential link between HCV-associated biochemical alterations and the direct cytopathic effect observed in this in vitro system. Using innovative computational modeling approaches, we further identified mitochondrial fatty acid oxidation enzymes, which are comparably regulated during in vitro infection and in patients with histological evidence of fibrosis, as possible targets through which HCV regulates temporal alterations in cellular metabolic homeostasis.

【 授权许可】

CC BY