Replication-transcription complex of coronaviruses: functions of individual viral non-structural subunits, properties and architecture of their complexes

Abstract

Coronaviruses (CoVs) belong to the subfamily Orthocoronavirinae of the family Coronaviridae. CoVs are enveloped (+) RNA viruses with unusually long genomes. Severe acute respiratory syndrome CoV (SARS-CoV), Middle East respiratory syndrome CoV (MERS-CoV), and the novel coronavirus (2019-nCoV, SARS-CoV-2) have been identif ied as causing global pandemics. Clinically tested vaccines are widely used to control rapidly spreading, acute, and often severe infections; however, effective drugs are still not available. The genomes of SARS-CoV-2 and SARS-CoV are approximately 80 % identical, while the genomes of SARS-CoV-2 and MERS-CoV are approximately 50 % identical. This indicates that there may be common mechanisms of coronavirus pathogenesis and, therefore, potential therapeutic targets for each virus may be the same. The enzymes and effector proteins that make up the replicationtranscription complex (RTC) of coronaviruses are encoded by a large replicase gene. These enzymes and effector proteins represent promising targets for potential therapeutic drugs. The enzyme targets include papain- and 3C-like cysteine proteinases that process two large viral polyproteins, RNA-dependent RNA polymerase, RNA helicase, viral genome-modifying enzymes, and enzymes with 3’–5’ exoribonuclease or uridylate-specif ic endonuclease activity. Currently, there are many studies investigating the complex molecular mechanisms involved in the assembly and function of the RTC. This review will encompass current, modern studies on the properties and complexes of individual non-structural subunits of the RTC, the structures of individual coronavirus RTC subunits, domain organization and functions of subunits, protein-protein interactions, properties and architectures of subunit complexes, the effect of mutations, and the identif ication of mutations affecting the viability of the virus in cell culture.

Classification, replication, and transcription of Nidovirales

“…The association of RTC with modified intracellular membranes is a feature commonly observed in the positive-stranded RNA viruses that infect animals. As for coronavirus, a set of replicases (NSP7, NSP8, NSP9, NSP10, NSP12, NSP13, NSP14, NSP15, and NSP16) assemble into the RTC which is responsible for synthesizing the negative-stranded intermediates, gRNA, and sg mRNAs ( Hagemeijer et al, 2010 ; Subissi et al, 2012 ; Kirchdoerfer and Ward, 2019 ; Chen et al, 2020 ; Hillen et al, 2020 ; Peng et al, 2020 ; Wang et al, 2020 ; Yan et al, 2020 , 2021 ; Mishchenko and Ivanisenko, 2022 ). The NSP7-NSP8-NSP12 complex plays a central role in the replication/transcription process of coronavirus.…”

Pathogenesis and Mechanisms of SARS-CoV-2 Infection in the Intestine, Liver, and Pancreas

“…Intracellularly, the viral genome is uncoated, released, and translated into various viral components. The replicase gene involves two open reading frames (ORFs) that encode the viral sections of the replication-transcription complex (RTC) [18,19]. Expression of the replicase gene and subsequent encoding of ORF1a and ORF1b leads to the production of replicase polyproteins, pp1a and pp1ab, respectively.…”