The interaction between the Hepatitis C proteins NS4B and NS5A is involved in viral replication

David, Naama; Yaffe, Yakey; Hagoel, Lior; Elazar, Menashe; Glenn, Jeffrey S.; Hirschberg, Koret; Sklan, Ella H.

doi:10.1016/j.virol.2014.10.021

Cited by 13 publications

(6 citation statements)

References 68 publications

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“…Tryptophan residues in several proteins play important role in protein–protein interactions . At the binding interface of the protein–protein interaction, the probability of having tryptophan residues is maximal compared to other amino acids .…”

Section: Discussionmentioning

confidence: 99%

Host–parasite interaction: multiple sites in the Plasmodium vivax tryptophan‐rich antigen PvTRAg38 interact with the erythrocyte receptor band 3

et al. 2016

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Tryptophan-rich antigens of malarial parasites interact with host molecules and play an important role in parasite survival. Merozoite expressed Plasmodium vivax tryptophan-rich antigen PvTRAg38 binds to human erythrocytes and facilitates parasite growth in a heterlologous Plasmodium falciparum culture system. Recently, we identified band 3 in human erythrocytes as one of its receptors, although the receptor-ligand binding mechanisms remain unknown. In the present study, using synthetic mutated peptides of PvTRAg38, we show that multiple amino acid residues of its 12 amino acid domain (KWVQWKNDKIRS) at position 197-208 interact with three different ectodomains of band 3 receptor on human erythrocytes. Our findings may help in the design of new therapeutic approaches for malaria.

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Section: Discussionmentioning

confidence: 99%

Host–parasite interaction: multiple sites in the Plasmodium vivax tryptophan‐rich antigen PvTRAg38 interact with the erythrocyte receptor band 3

et al. 2016

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“…The locations of the input mutation and the rescue reversion in the present study were striking. Unlike the previous two studies, where the input mutation resides on helix 1 of the C-terminal domain of NS4B and the rescue reversion or site of interaction resides on domain I of NS5A (52,53), in the present study, the input mutation resides at the NS5A N-terminal anchor helix region, and the rescue reversion resides on helix 2 of the C-terminal domain of NS4B. Considering that NS4B interacts directly with NS5A during replication, if the findings of the present study are combined with the findings of others (40,52,53), and if one assumes that the genetic interactions observed by these efforts represent physical contact surfaces, the arrangement of the input mutation and the rescue reversion suggests that the interaction between NS5A and NS4B occurs at multiple sites in a parallel head-to-tail orientation on the surface of the ER.…”

Section: Figmentioning

confidence: 82%

“…So far, several studies demonstrated the interaction between NS4B and NS5A but with limited information about the nature of the interaction. A recent study showed that the interaction between domain I of NS5A and helix 1 of the C-terminal domain of NS4B is involved in HCV RNA replication (52). In another study, revertant analysis showed that the effect of mutations in helix 1 of the C-terminal domain of NS4B is rescued by an intergenic reversion situated around the center of domain I of NS5A (53).…”

Section: Figmentioning

confidence: 99%

Interaction between Nonstructural Proteins NS4B and NS5A Is Essential for Proper NS5A Localization and Hepatitis C Virus RNA Replication

Biswas

Treadaway

Tellinghuisen

2016

J Virol

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The hepatitis C virus NS5A protein is tethered to cellular membranes via an amphipathic amino-terminal helix that is inserted in-plane into the outer endoplasmic reticulum (ER)-derived membrane leaflet. The charged face of the helix faces the cytoplasm and may contribute to interactions involved in replicase assembly and function. Using an aggressive charge flip mutagenesis strategy, we identified a number of essential residues for replication on the charged face of the NS5A anchor and identified a double charge face mutant that is lethal for RNA replication but generates suppressor mutations in the carboxy-terminal helix of the NS4B protein. This suppressor restores RNA replication of the NS5A helix double flip mutant (D1979K/D1982K) and, interestingly, seems to function by restoring the proper localization of NS5A to the viral replicase. These data add to our understanding of the complex organization and assembly of the viral replicase via NS4B-NS5A interactions. IMPORTANCEInformation about the functional role of the cytosolic face of the NS5A anchoring helix remains obscure. In this study, we show that while the hydrophobic face of the NS5A anchor helix mediates membrane association, the polar cytosolic face of the helix plays a key role during hepatitis C virus (HCV) replication by mediating the interaction of NS5A with other HCV nonstructural proteins via NS4B. Such an interaction determines the subcellular localization of NS5A by engaging NS5A in the HCV replication process during the formation of a functional HCV replication complex. Thus, collectively, it can be stated that the findings in the present study provide further information about the interactions between the HCV nonstructural proteins during HCV RNA replication and provide a platform to gain more insights about the molecular architecture of HCV replication complexes. Hepatitis C virus (HCV) is an enveloped, positive-sense, singlestranded RNA virus belonging to Hepacivirus genus within the Flaviviridae family. The HCV open reading frame (ORF) encodes a polyprotein of ϳ3,011 amino acids (aa), which is cleaved co-and posttranslationally by viral and host proteases into 10 viral proteins: the core; the envelope glycoproteins E1 and E2; the viroporin p7; and the nonstructural (NS) proteins NS2, NS3, NS4A, NS4B, NS5A, and NS5B. Among the NS proteins, NS2 with the protease activity is required for virion assembly; NS3 is a multifunctional protein with serine protease activity at the N-terminal region, while the C-terminal portion of the protein holds helicase/ nucleotide triphosphatase (NTPase) activity; NS4A acts as a cofactor for the NS3 serine protease; NS4B serves the scaffold for the HCV replication complex (RC) by inducing the formation of the membranous web (MW); NS5A is a phosphoprotein that plays a key role in HCV RNA replication and viral assembly processes; and NS5B is the RNA-dependent RNA polymerase (1-5).Like all other positive-strand RNA viruses, HCV RNA replicates in close association with cellular membranes. HCV alters the en...

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“…NS4B also forms oligomeric complexes via self-interaction, which is required for HCV RNA replication, in addition to the above-mentioned RO formation [ 30 , 37 , 38 ]. The interaction between the NS4B and NS5A is reportedly involved in viral replication [ 129 , 130 ].…”

Section: Genome Replicationmentioning

confidence: 99%

Hepatitis C Viral Replication Complex

Yang

2021

Viruses

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The life cycle of the hepatitis C virus (HCV) can be divided into several stages, including viral entry, protein translation, RNA replication, viral assembly, and release. HCV genomic RNA replication occurs in the replication organelles (RO) and is tightly linked to ER membrane alterations containing replication complexes (proteins NS3 to NS5B). The amplification of HCV genomic RNA could be regulated by the RO biogenesis, the viral RNA structure (i.e., cis-acting replication elements), and both viral and cellular proteins. Studies on HCV replication have led to the development of direct-acting antivirals (DAAs) targeting the replication complex. This review article summarizes the viral and cellular factors involved in regulating HCV genomic RNA replication and the DAAs that inhibit HCV replication.

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The interaction between the Hepatitis C proteins NS4B and NS5A is involved in viral replication

Cited by 13 publications

References 68 publications

Host–parasite interaction: multiple sites in the Plasmodium vivax tryptophan‐rich antigen PvTRAg38 interact with the erythrocyte receptor band 3

Host–parasite interaction: multiple sites in the Plasmodium vivax tryptophan‐rich antigen PvTRAg38 interact with the erythrocyte receptor band 3

Interaction between Nonstructural Proteins NS4B and NS5A Is Essential for Proper NS5A Localization and Hepatitis C Virus RNA Replication

Hepatitis C Viral Replication Complex

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