A proteome-wide mapping of interactions between hepatitis C virus (HCV) and human proteins was performed to provide a comprehensive view of the cellular infection. A total of 314 protein-protein interactions between HCV and human proteins was identified by yeast two-hybrid and 170 by literature mining. Integration of this data set into a reconstructed human interactome showed that cellular proteins interacting with HCV are enriched in highly central and interconnected proteins. A global analysis on the basis of functional annotation highlighted the enrichment of cellular pathways targeted by HCV. A network of proteins associated with frequent clinical disorders of chronically infected patients was constructed by connecting the insulin, Jak/STAT and TGFb pathways with cellular proteins targeted by HCV. CORE protein appeared as a major perturbator of this network. Focal adhesion was identified as a new function affected by HCV, mainly by NS3 and NS5A proteins.
Autophagy is a conserved degradative pathway used as a host defense mechanism against intracellular pathogens. However, several viruses can evade or subvert autophagy to insure their own replication. Nevertheless, the molecular details of viral interaction with autophagy remain largely unknown. We have determined the ability of 83 proteins of several families of RNA viruses (Paramyxoviridae, Flaviviridae, Orthomyxoviridae, Retroviridae and Togaviridae), to interact with 44 human autophagy-associated proteins using yeast two-hybrid and bioinformatic analysis. We found that the autophagy network is highly targeted by RNA viruses. Although central to autophagy, targeted proteins have also a high number of connections with proteins of other cellular functions. Interestingly, immunity-associated GTPase family M (IRGM), the most targeted protein, was found to interact with the autophagy-associated proteins ATG5, ATG10, MAP1CL3C and SH3GLB1. Strikingly, reduction of IRGM expression using small interfering RNA impairs both Measles virus (MeV), Hepatitis C virus (HCV) and human immunodeficiency virus-1 (HIV-1)-induced autophagy and viral particle production. Moreover we found that the expression of IRGM-interacting MeV-C, HCV-NS3 or HIV-NEF proteins per se is sufficient to induce autophagy, through an IRGM dependent pathway. Our work reveals an unexpected role of IRGM in virus-induced autophagy and suggests that several different families of RNA viruses may use common strategies to manipulate autophagy to improve viral infectivity.
The procyclic form of Trypanosoma brucei is a parasitic protozoan that normally dwells in the midgut of its insect vector. In vitro, this parasite prefers D-glucose to L-proline as a carbon source, although this amino acid is the main carbon source available in its natural habitat. Here, we investigated how L-proline is metabolized in glucose-rich and glucose-depleted conditions. Analysis of the excreted end products of 13 C-enriched L-proline metabolism showed that the amino acid is converted into succinate or L-alanine depending on the presence or absence of D-glucose, respectively. The fact that the pathway of L-proline metabolism was truncated in glucose-rich conditions was confirmed by the analysis of 13 separate RNA interference-harboring or knock-out cell lines affecting different steps of this pathway. For instance, RNA interference studies revealed the loss of succinate dehydrogenase activity to be conditionally lethal only in the absence of D-glucose, confirming that in glucose-depleted conditions, L-proline needs to be converted beyond succinate. In addition, depletion of the F 0 /F 1 -ATP synthase activity by RNA interference led to cell death in glucose-depleted medium, but not in glucose-rich medium. This implies that, in the presence of D-glucose, the importance of the F 0 /F 1 -ATP synthase is diminished and ATP is produced by substrate level phosphorylation. We conclude that trypanosomes develop an elaborate adaptation of their energy production pathways in response to carbon source availability.Trypanosomatids are parasitic protozoa, among which several species cause serious diseases in humans such as sleeping sickness (Trypanosoma brucei), Chagas disease (Trypanosoma cruzi), and leishmaniasis (Leishmania spp.). These pathogenic trypanosomatids have developed a digenetic lifestyle with one or several vertebrate hosts (including humans) and a hematophagous insect vector that allows their transmission between vertebrate hosts. Recently, the genome sequencing projects of T. brucei (TREU927 strain) (1), T. cruzi (CL Brener strain) (2), and Leishmania major (Friedlin strain) (3) have been completed, providing wonderful tools to determine their metabolic complexities (1).Trypanosomatids depend on the carbon sources present in their hosts for their energy metabolism (4). For example, the trypomastigote forms of T. brucei and T. cruzi (bloodstream forms) use D-glucose, which is abundant in the fluids of their vertebrate host(s) (5, 6). In contrast, the insect vectors obtain their energy from L-proline and/or L-glutamine, the prominent constituent of their hemolymph and tissue fluids (7). Consequently, the insect stages of T. brucei and T. cruzi rely on amino acid catabolism, with a preference for L-proline. However, these parasites prefer D-glucose when grown in medium rich in this sugar. Because glucose-rich media are routinely used to grow these parasites, D-glucose metabolism has received the most attention, and relatively little is known about their amino acid metabolism. Recent advances in underst...
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