The Putative Roles and Functions of Indel, Repetition and Duplication Events in Alphavirus Non-Structural Protein 3 Hypervariable Domain (nsP3 HVD) in Evolution, Viability and Re-Emergence

Abstract

Alphavirus non-structural proteins 1–4 (nsP1, nsP2, nsP3, and nsP4) are known to be crucial for alphavirus RNA replication and translation. To date, nsP3 has been demonstrated to mediate many virus–host protein–protein interactions in several fundamental alphavirus mechanisms, particularly during the early stages of replication. However, the molecular pathways and proteins networks underlying these mechanisms remain poorly described. This is due to the low genetic sequence homology of the nsP3 protein among the alphavirus species, especially at its 3′ C-terminal domain, the hypervariable domain (HVD). Moreover, the nsP3 HVD is almost or completely intrinsically disordered and has a poor ability to form secondary structures. Evolution in the nsP3 HVD region allows the alphavirus to adapt to vertebrate and insect hosts. This review focuses on the putative roles and functions of indel, repetition, and duplication events that have occurred in the alphavirus nsP3 HVD, including characterization of the differences and their implications for specificity in the context of virus–host interactions in fundamental alphavirus mechanisms, which have thus directly facilitated the evolution, adaptation, viability, and re-emergence of these viruses.

The clinical progress and challenges of mRNA vaccines

“…Unlike nonreplicating mRNA vaccines, which only serve as templates for the translation of antigenic proteins, saRNA vaccines often encode four extra proteins besides the vaccine antigen or gene of interest. These four extra proteins belong to the nonstructural proteins 1–4 (nsP1–nsP4) derived from viruses (mainly alphaviruses, e.g., Venezuelan equine encephalitis [VEE] or Sindbis virus [SIN]), and function as the replication machinery of viruses to self‐amplify the genome RNAs intracellularly (Abdullah et al, 2021). Thus, in terms of structure, saRNA retains, in addition to the conventional elements of nonreplicating mRNA, a long ORF sequence that encodes a viral replicase (nsP1–nsP4) to amplify mRNA in the host cells.…”

Determinants of Chikungunya and O’nyong-Nyong Virus Specificity for Infection of Aedes and Anopheles Mosquito Vectors

“…G3BPs are RNA-binding proteins involved in stress granule formation, but their cellular functions are not well understood [ 54 , 104 , 105 , 106 , 107 ]. The interaction between nsP3 and GFBP/Rasputin is conserved among alphaviruses both in mammalian and insect cells [ 106 , 107 , 108 , 109 ]. Rasputin in Ae.…”

Identification of mosquito proteins that differentially interact with alphavirus nonstructural protein 3, a determinant of vector specificity

“…Alphavirus nsP3 is composed of three domains: the N-terminal macrodomain, the central alphavirus unique domain (AUD), and the C-terminal highly variable domain (HVD). The macrodomain hydrolyses ADP-ribose phosphate and binds polyadenylate and poly ADP-ribose [18][19][20]. ADP-ribosylation is used as a cellular signal in many processes, including stress granule formation, DNA repair, gene regulation, and apoptosis.…”