ReviewFree Access
Post-translational modifications of coronavirus proteins: roles and function
Published Online:21 May 2018https://doi.org/10.2217/fvl-2018-0008
Coronaviruses are a family of enveloped RNA viruses causing diseases
in both animals and humans. Infection by animal coronaviruses, such as
infectious bronchitis virus (IBV) and transmissible gastroenteritis
virus (TGEV), reduces the yield and quality of domestic animals and
causes great economic loss to the industry worldwide [1], whereas the extremely contagious mouse hepatitis virus (MHV) is presumably the most important pathogen of laboratory mice [2]. Human coronaviruses, such as HCoV-229E and HCoV-OC43, account for a significant percentage of common colds in adults [3,4].
Notably, the newly emerged, highly pathogenic human coronaviruses
severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East
respiratory syndrome coronavirus (MERS-CoV) cause severe diseases with
high mortality rates [5,6].
The same bat origin of both SARS-CoV and MERS-CoV suggests that
coronavirus has the inherent ability to cross the species barrier to
become lethal human pathogens. Therefore, a better understanding of the
biology and pathogenesis of this family of viruses is critical in face
of the threat of future epidemics.
Taxonomically, the family Coronaviridae is divided into two subfamilies:
Coronavirinae and Torovirinae.
The subfamily Coronavirinae is further classified into four genera, namely Alphacoronavirus, Betacoronavirus, Gammacoronavirus and Deltacoronaviruses, based on initial antigenic relationship and later genome sequence alignment [7]. Within the genus Betacoronavirus, four lineages (A, B, C and D) can be phylogenetically distinguished. While the prototypic MHV is a lineage A Betacoronavirus, SARS-CoV and MERS-CoV belong to lineage B and C, respectively. Current evidence suggests that Alphacoronavirus and Betacoronavirus may evolve from bat coronaviruses and later establish mammalian tropism, whereas Gammacoronavirus and Deltacoronavirus may originate from avian coronaviruses and thus mainly infect avian hosts [8].
Morphologically, coronaviruses are spherical or pleomorphic in shape with an average diameter of 80–120 nm. Under the electron microscope, the virions are characterized by surface projections constituted by the trimeric S-glycoprotein [9]. In some Betacoronaviruses, a second type of shorter projections, contributed by the homodimeric HE protein, can be observed [10]. The most abundant protein in the virion is the M-glycoprotein, which embeds into the envelope and provides structural support to the virion. The E protein is a small, integral membrane protein present at a low amount in the virion, but it plays an essential role during virion assembly and release [11,12]. Inside the envelope, the helically symmetric nucleocapsid is comprised of the RNA genome closely associated with the N protein in a beads-on-a-string fashion. The positive sense, nonsegmented, ssRNA genome, ranging from 27,000 to 32,000 nucleotides in size, is the largest RNA genome known to date.
The replication cycle of coronavirus starts with the binding of the S protein to its cognate receptor(s) on the host cell surface (Figure 1), which triggers a conformational change in the S2 subunit and results in the fusion between the viral envelope and the cellular membrane, thereby delivering the nucleocapsid into the cytoplasm [9]. After uncoating, the genomic RNA containing a 5′-cap and a 3′-poly(A) tail is recognized by the host translation machinery to synthesize a polyprotein 1a (pp1a), as well as a larger polyprotein 1ab (pp1ab) in a process involving ribosomal frameshifting [13]. Autoproteolytic cleavage of pp1a and pp1ab produces 15–16 nonstructural proteins (nsps) with diverse functions. Among them, nsp3 and nsp5 encode the papain-like protease (PLPro) activity and the chymotrypsin-like main protease (Mpro) activity, respectively, whereas nsp12 encodes the critical RNA-dependent RNA polymerase (RdRp) activity [14,15]. In the replication/transcription complex closely associated with virus-induced double membrane vesicles (DMVs) or spherules, positive-sense progeny genomic RNA is synthesized from the negative-sense intermediate. On the other hand, a nested set of subgenomic RNA (sgRNA) species is synthesized by discontinuous transcription of the genome, from which structural and accessory proteins are translated. Transmembrane structural proteins (S, M and E) are synthesized, folded and modified in the endoplasmic reticulum (ER) and transported to the ER–Golgi intermediate compartment, where they interact with the encapsidated genome to assemble progeny virions. At last, virions budded into the ER–Golgi intermediate compartment are transported inside smooth-wall vesicles and released to the extracellular milieu via the secretory pathway, thereby starting a new round of viral replication. Infection of some coronaviruses also causes the fusion of the infected cell with neighboring uninfected cells, resulting in a large multinucleated syncytium. The replication cycle of coronavirus is shown in Figure 1.
Taxonomically, the family Coronaviridae is divided into two subfamilies:
Coronavirinae and Torovirinae.
The subfamily Coronavirinae is further classified into four genera, namely Alphacoronavirus, Betacoronavirus, Gammacoronavirus and Deltacoronaviruses, based on initial antigenic relationship and later genome sequence alignment [7]. Within the genus Betacoronavirus, four lineages (A, B, C and D) can be phylogenetically distinguished. While the prototypic MHV is a lineage A Betacoronavirus, SARS-CoV and MERS-CoV belong to lineage B and C, respectively. Current evidence suggests that Alphacoronavirus and Betacoronavirus may evolve from bat coronaviruses and later establish mammalian tropism, whereas Gammacoronavirus and Deltacoronavirus may originate from avian coronaviruses and thus mainly infect avian hosts [8].
Morphologically, coronaviruses are spherical or pleomorphic in shape with an average diameter of 80–120 nm. Under the electron microscope, the virions are characterized by surface projections constituted by the trimeric S-glycoprotein [9]. In some Betacoronaviruses, a second type of shorter projections, contributed by the homodimeric HE protein, can be observed [10]. The most abundant protein in the virion is the M-glycoprotein, which embeds into the envelope and provides structural support to the virion. The E protein is a small, integral membrane protein present at a low amount in the virion, but it plays an essential role during virion assembly and release [11,12]. Inside the envelope, the helically symmetric nucleocapsid is comprised of the RNA genome closely associated with the N protein in a beads-on-a-string fashion. The positive sense, nonsegmented, ssRNA genome, ranging from 27,000 to 32,000 nucleotides in size, is the largest RNA genome known to date.
The replication cycle of coronavirus starts with the binding of the S protein to its cognate receptor(s) on the host cell surface (Figure 1), which triggers a conformational change in the S2 subunit and results in the fusion between the viral envelope and the cellular membrane, thereby delivering the nucleocapsid into the cytoplasm [9]. After uncoating, the genomic RNA containing a 5′-cap and a 3′-poly(A) tail is recognized by the host translation machinery to synthesize a polyprotein 1a (pp1a), as well as a larger polyprotein 1ab (pp1ab) in a process involving ribosomal frameshifting [13]. Autoproteolytic cleavage of pp1a and pp1ab produces 15–16 nonstructural proteins (nsps) with diverse functions. Among them, nsp3 and nsp5 encode the papain-like protease (PLPro) activity and the chymotrypsin-like main protease (Mpro) activity, respectively, whereas nsp12 encodes the critical RNA-dependent RNA polymerase (RdRp) activity [14,15]. In the replication/transcription complex closely associated with virus-induced double membrane vesicles (DMVs) or spherules, positive-sense progeny genomic RNA is synthesized from the negative-sense intermediate. On the other hand, a nested set of subgenomic RNA (sgRNA) species is synthesized by discontinuous transcription of the genome, from which structural and accessory proteins are translated. Transmembrane structural proteins (S, M and E) are synthesized, folded and modified in the endoplasmic reticulum (ER) and transported to the ER–Golgi intermediate compartment, where they interact with the encapsidated genome to assemble progeny virions. At last, virions budded into the ER–Golgi intermediate compartment are transported inside smooth-wall vesicles and released to the extracellular milieu via the secretory pathway, thereby starting a new round of viral replication. Infection of some coronaviruses also causes the fusion of the infected cell with neighboring uninfected cells, resulting in a large multinucleated syncytium. The replication cycle of coronavirus is shown in Figure 1.
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