Role of Host-Mediated Post-Translational Modifications (PTMs) in RNA Virus Pathogenesis

Abstract

Being opportunistic intracellular pathogens, viruses are dependent on the host for their replication. They hijack host cellular machinery for their replication and survival by targeting crucial cellular physiological pathways, including transcription, translation, immune pathways, and apoptosis. Immediately after translation, the host and viral proteins undergo a process called post-translational modification (PTM). PTMs of proteins involves the attachment of small proteins, carbohydrates/lipids, or chemical groups to the proteins and are crucial for the proteins' functioning. During viral infection, host proteins utilize PTMs to control the virus replication, using strategies like activating immune response pathways, inhibiting viral protein synthesis, and ultimately eliminating the virus from the host. PTM of viral proteins increases solubility, enhances antigenicity and virulence properties. However, RNA viruses are devoid of enzymes capable of introducing PTMs to their proteins. Hence, they utilize the host PTM machinery to promote their survival. Proteins from viruses belonging to the family: Togaviridae, Flaviviridae, Retroviridae, and Coronaviridae such as chikungunya, dengue, zika, HIV, and coronavirus are a few that are well-known to be modified. This review discusses various host and virus-mediated PTMs that play a role in the outcome during the infection.

Keywords: RNA viruses; acetylation; glycosylation; host factors; pathogenesis; phosphorylation; post-translation modification; ubiquitination; virulence factors.

Figure 1

Overview of various post-translational modifications of virus and host proteins having an important role during viral infections. Based on the biochemical nature of attached moieties, post-translational modification (PTMs) can be categorized into modification by small protein groups (ubiquitination, ISGylation, SUMOylation, NEDDylation), carbohydrates moieties (glycosylation, ADP ribosylation), lipids (palmitoylation, myristoylation, and prenylation), and small chemical groups (phosphorylation, methylation, and acetylation). The proteins upon modification result in loss/gain in function, which modulates the virus’s life cycle and host response to virus infection.

Figure 2

Small protein-based post-translational modifications during viral infection. Ubiquitin and ubiquitin-like molecules such as ISG15, NEDD8, and SUMO play an essential role during viral infection. Specific enzymes such as E1, E2, and E3 ligases are involved in the modification process. The anti-viral effect is exerted by inducing IFN response, destabilizing viral proteins, or targeting viral proteins to their degradation. These modifications also exert a pro-viral impact by improving the enzymatic activity or interactions of the viral proteins, which promotes viral replication and degradation of host proteins involved in immune response proteins.

Figure 3

Carbohydrate and lipid moieties based post-translational modification. Carbohydrates based PTMs includes glycosylation and ADP ribosylation. Glycosylation plays a role in enhancing viral replication by increasing receptor binding, protein solubilization, virulence, and antigenicity of viral proteins. Glycosylation is also involved in the inhibition of viral replication. Mannose-binding lectin (MBL) binds to non-self glycoproteins such as viral proteins, activates the complement pathway, and inhibits viral replication. PARPs (Poly ADP ribose polymerases) mediated ADP ribosylation of viral proteins targets them for degradation, thus acting as anti-viral. The modification also works as pro-viral by targeting protein involved in the immune response during viral infection. Viruses also favors their growth by removing the ADP ribosylation, thereby favoring growth. Lipid molecules such as palmitoylation, myristoylation, and prenylation. The modifications favors viral replication by assisting in viral assembly. In contrast, these inhibit viral replication by triggering IFN response, bind to viral RNA, and inhibit viral replication or block membrane fusion.

Figure 4

Small molecules/chemical group based PTMs. Small chemical groups such as phosphate, methyl, acetyl, and ionic groups are added to proteins by specific enzymes. Phosphorylation involves kinases which transfer phosphate group and play a role in protein-protein interaction, thereby affecting protein localization and signaling pathways. Methylation of host and viral proteins involved methyl group transfer from substrate protein by the help of methyltransferases. Methylation plays a role in modulating gene expression by regulating chromatin condensation, regulating both host gene expression and transcription of integrated viral genomes. Acetylation of histone proteins regulate gene expression and microtubule organization and affect viral replication.