Chem Biol Drug Des. Bruning A, Aatola H, Toivola H, Ikonen N, Savolainen-Kopra C, Blomqvist S, et al. However, the new virion also remains attached to the membrane as well as the previous virion by a small membranous neck. MBio. The autophagy machinery is required to initiate hepatitis C virus replication. Using SignalP, Wu, Zhang [79] reported a predicted signal peptide cleavage site at the N-terminus of the SARS-CoV E protein. The PBM domain was either mutated or deleted but reverted to a pathogenic state after several passages in Vero E6 host cells. Aside from this, it is of therapeutic importance that more E interaction partners be identified as inhibitors of p38 mitogen-activated protein kinase (MAPK) were shown to increase the survival rate of mice, protecting them from a lethal infection [18, 158]. A renewed interest in coronaviral research has led to the discovery of several novel human CoVs and since then much progress has been made in understanding the CoV life cycle. PubMed Central Crawford SE, Hyser JM, Utama B, Estes MK. Epidemiology and cause of severe acute respiratory syndrome (SARS) in Guangdong, People's Republic of China, in February, 2003. Mol Biol Cell. Corse E, Machamer CE. However, this increase in pH was found only in cells expressing a monomeric form of IBV E and not the oligomeric form as required for viroporin formation. Blocking ion channel activity with amantadine significantly inhibited activation of the inflammasome, demonstrating an association between E viroporin activity and inflammation. The hydrophobic domain of infectious bronchitis virus E protein alters the host secretory pathway and is important for release of infectious virus. Conversely, the release of influenza virions is mediated by the M2 protein in an ESCRT-independent manner. Synthetic peptides that correspond to the SARS-CoV E TMD can form dimers, trimers, and pentamers, demonstrating the importance of the TMD in CoV E homotypic interactions [137]. Concern has been raised over the possibility of epitope-tagged E proteins affecting its localisation, but both FLAG-tagged and untagged versions of SARS-CoV E demonstrate this distribution pattern [73, 81, 92]. 1993;67(9):558594. Futur Virol. Mutant N15A reverted by incorporating a single mutation that led to an amino acid change at the same position (A15D), creating a more stable mutant. Conversely, helical structure formation can be affected by up to nine residues away from the central residue and would benefit from a larger window size [103]. Westerbeck and Machamer [90] used both infected and transfected cells and reported the presence of two different forms of the IBV E protein, each associated with a specific function. J Virol. Live, attenuated vaccines and fusion inhibitors have proven promising, but both also require an intimate knowledge of CoV molecular biology [29, 31,32,33,34,35,36]. Nucleocapsid-independent assembly of coronavirus-like particles by co-expression of viral envelope protein genes. Hung AY, Sheng M. PDZ domains: structural modules for protein complex assembly. 2018;92(7):e0215217. 2002;277(43):4043441. Engineering a replication-competent, propagation-defective Middle East respiratory syndrome coronavirus as a vaccine candidate. 2004;279(11):1013641. An S, Chen C-J, Yu X, Leibowitz JL, Makino S. Induction of apoptosis in murine coronavirus-infected cultured cells and demonstration of E protein as an apoptosis inducer. Lopez LA, Riffle AJ, Pike SL, Gardner D, Hogue BG. Standard XIII Biology Coronaviruses primarily infect birds and mammals, causing a variety of lethal diseases that particularly impact the farming industry [3, 4]. 2011;85(22):1154456. Biochem J. volume16, Articlenumber:69 (2019) Genetic variability of human coronavirus OC43-, 229E-, and NL63-like strains and their association with lower respiratory tract infections of hospitalized infants and immunocompromised patients. Despite the deletion of some viral genes, the viral life cycle continues, suggesting that other viral genes can compensate for this loss. Principles governing amino acid composition of integral membrane proteins: application to topology prediction1. 2014;5:296. Tusnady GE, Simon I. Roberts KL, Leser GP, Ma C, Lamb RA. Castao-Rodriguez C, Honrubia JM, Gutirrez-lvarez J, DeDiego ML, Nieto-Torres JL, Jimenez-Guardeo JM, et al. 2013;8(10):e76469. 2010;402(2):28191. statement and Google Scholar. Cell. Proc Natl Acad Sci. These envelope glycoproteins (EnvGP) evolved in order to combine two features. The PBM of SARS-CoV E is found in the last four amino acids (DLLV) of its C-terminus [1, 82]. J Virol. Bat-to-human: Spike features determining host jumpof coronaviruses SARS-CoV, MERS-CoV, and beyond. Proc Natl Acad Sci. Ruch TR, Machamer CE. Yuan B, Campbell S, Bacharach E, Rein A, Goff SP. 1997;16(12):351932. 2005;64:165230. 2013;18(1718):80717. CAS Grice A, Kerr I, Sansom M. Ion channels formed by HIV-1 Vpu: a modelling and simulation study. 2007;38(3):24450. 2018;13(6):40530. The envelope is acquired by the capsid from an intracellular membrane in the virus' host; examples include the inner nuclear membrane, the Golgi membrane, and the cell's outer membrane. 2008;105(29):1020914. Interestingly, PRRSV activates autophagy machinery, possibly to enhance viral replication as certain components of autophagy are required for MHV replication [280, 281]. Role of the spike glycoprotein of human Middle East respiratory syndrome coronavirus (MERS-CoV) in virus entry and syncytia formation. 1990;64(2):6219. 2012;8(11):e1002749. In N-linked glycosylation, oligosaccharide moieties are attached to specific asparagine residues located in the consensus sequence Asn-X-Ser/Thr. Likewise, residue N48 in SARS-CoV E was also shown not to be glycosylated and proposed to be non-functional for the same reason [73]. van Kuppeveld FJ, Hoenderop JG, Smeets RL, Willems PH, Dijkman HB, Galama JM, et al. 1997;94(21):113016. Virology. Front Microbiol. To emphasize the unique nature of viral nucleic acid and its role in the infection process. Role of the coronavirus E viroporin protein transmembrane domain in virus assembly. 2013;66:JVI. Co-expression of SARS-CoV nsps 3, 4, and 6 can induce membrane rearrangements that resemble the DMVs and CMs observed in CoV-infected cells [176]. Larger, protein-based therapies, on the other hand, make use of insulin, growth factors, and engineered antibodies, that form many more, and much stronger, interactions, making these therapies more potent and selective for their targets. Most likely then, instead of coordinating viral assembly, the function of E is rather to induce membrane curvature of the viral envelope, thereby allowing CoV particles to acquire their characteristic spherical shape and morphology. The ORF4a protein of human coronavirus 229E functions as a viroporin that regulates viral production. Cell entry of enveloped viruses - PubMed J Biol Chem. Human respiratory coronavirus HKU1 versus other coronavirus infections in Italian hospitalised patients. The studies in this review have shown that CoV E could be involved in multiple aspects of the viral replication cycle: from assembly and induction of membrane curvature to scission or budding and release to apoptosis, inflammation and even autophagy. Stewart ML, Fire E, Keating AE, Walensky LD. 2009;49(1):6071. MSystems. Article 2009;83(9):465269. While some enveloped viruses, like influenza A virus, encode their own scission proteins, other viruses rely on the host cells endosomal sorting complex required for transport (ESCRT) to accomplish this [179]. Premkumar A, Wilson L, Ewart G, Gage P. Cation-selective ion channels formed by p7 of hepatitis C virus are blocked by hexamethylene amiloride. Some viroporins have been implicated in the release of viruses, but it is not yet known whether the release is mediated by the ion channel activity of the proteins [187, 223,224,225,226]. Identification of the mechanisms causing reversion to virulence in an attenuated SARS-CoV for the design of a genetically stable vaccine. Infectious bronchitis virus E protein is targeted to the Golgi complex and directs release of virus-like particles. Ectodomain The portion of the transmembrane protein that remains exposed outside of the cell or virus particle. FEBS Lett. It is interesting to note that in both cases SARS-CoV E and IBV E followed a similar trend in their reversion: mutations at N15A and T16A both reverted by substitution of a single residue, whereas mutations at V25F and A26F produced revertants by acquisition of multiple residues. 2004;341(3):76979. Science. 1-1C, ,D; D; Plate 1-1C). 6.2 The Viral Life Cycle - Microbiology | OpenStax J Biol Chem. 2018;8:2003. InTech. The authors also reported that the other viral structural proteins did not appear to significantly influence the localization of the E protein, concluding that localization of SARS-CoV E occurs at the ERGIC, whether expressed alone or during an infection. PLoS Comput Biol. Parthasarathy K, Ng L, Lin X, Liu DX, Pervushin K, Gong X, et al. Rotavirus disrupts calcium homeostasis by NSP4 viroporin activity. 6) [253,254,255]. J Mol Biol. Intriguingly, the V25F mutants appeared as early as 2 days after mice were infected where revertant mutant T30I surpassed the growth of the original virus by day two. PubMed Central Based on genetic and antigenic criteria, CoVs have been organised into three groups: -CoVs, -CoVs, and -CoVs (Table1) [1, 2]. The evolution of the viral envelope is made more puzzling by the fact that nonenveloped viruses are able to infect a diverse range of hosts across the tree of life. 2003;552(1):2834. 2003;100(20):1164651. Nat Chem Biol. Expression and purification of coronavirus envelope proteins using a modified -barrel construct. Jimenez-Guardeo JM, Nieto-Torres JL, DeDiego ML, Regla-Nava JA, Fernandez-Delgado R, Castao-Rodriguez C, et al. Molecular Expressions Cell Biology: Virus Structure - National MagLab The p7 polypeptide of hepatitis C virus is critical for infectivity and contains functionally important genotype-specific sequences. Lamirande EW, DeDiego ML, Roberts A, Jackson JP, Alvarez E, Sheahan T, et al. Nature. Nevertheless, some proteins prove challenging to isolate and not all biochemical techniques offer the needed high-resolution structural detail, in which case prediction programs are a good alternative and offer valuable insight into the predicted outcomes [101]. 2006;7(1):68. 2011;85(12):5794803. A single polar residue and distinct membrane topologies impact the function of the infectious bronchitis coronavirus E protein. 2010;463(7282):813. Viruses - National Geographic Society Palmitoylation of IBV E does not affect its localization to the Golgi region, as cysteine-mutated E proteins are indistinguishable from their palmitoylated counterparts [93]. CAS In its infective form, outside the cell, a virus particle is called a virion. Protein palmitoylation and dynamic modulation of protein function. 2000;74(11):496778. Microbes Infect. 2016;55(25):34936. Improving the accuracy of transmembrane protein topology prediction using evolutionary information. If, however, the UPR is prolonged and irreversible, apoptosis will be initiated [230]. 2013;4(5):e0065013. Assessing activity and inhibition of MERS-CoV papain-like and 3C-like proteases using luciferase-based biosensors. Bioinformatics. 2008;95(6):L3941. Interestingly, localisation of N to the endoplasmic reticulum (ER)-Golgi region has proposed a function for it in assembly and budding [50, 51]. Thorax. 2013;4(4):e0052413. A live attenuated severe acute respiratory syndrome coronavirus is immunogenic and efficacious in golden Syrian hamsters. Virology. Capsid contruction varies greatly among viruses, with most being specialized for a particular virus's host organism. Palmitoylation functions in the subcellular trafficking of proteins between membrane compartments and can also modulate protein-protein interactions (PPIs) [110, 111]. 2010;6(9):e1001087. By using this website, you agree to our J Mol Biol. Mutation of the hydrophobic region of the helix also significantly reduced viral release in vivo, confirming the importance of the 17-amino-acid-helix in the release of the influenza virus in vivo as well. Considering these studies, along with the ability of SARS-CoV to channel Ca2+, it is not inconceivable that CoV E viroporin could induce autophagy in CoV-infected cells by increasing cytosolic Ca2+. 2012;586(4):38491. Induction of apoptosis by the severe acute respiratory syndrome coronavirus 7a protein is dependent on its interaction with the Bcl-XL protein. Lou Z, Sun Y, Rao Z. Other viruses use viroporins to stimulate an immune response as part of their pathogenicity, including the E protein of PRRSV [241,242,243]. 1997;71(12):927884. Influenza B virus BM2 protein has ion channel activity that conducts protons across membranes. Comparative and phylogenetic analysis of SARS-CoV E revealed that a substantial portion of the TMD consists of the two nonpolar, neutral amino acids, valine and leucine, lending a strong hydrophobicity to the E protein [79]. Lau SK, Woo PC, Li KS, Huang Y, Tsoi H-W, Wong BH, et al. MBio. A structural analysis of M protein in coronavirus assembly and morphology. Pre-fusion structure of a human coronavirus spike protein. It would be interesting to see if any of these serially passaged PBM mutants are still capable of host cell protein interaction and whether the mutations allow the virus to retain its pathogenicity in both in vivo and in vitro systems. Interestingly, an amphipathic -helix is predicted to be located in the TMD of CoV E and has even been confirmed in some of the CoVs [72, 76, 77, 135, 136, 138, 140, 159, 185, 186]. J Clin Virol. As more viral PPIs for CoV E are identified, the repertoire of stapled peptide targets also expands making it easier to limit viral replication, propagation, and even pathogenesis. PubMed The authors would like to thank Bianca Gordon for proofreading the draft and providing valuable feedback as well as Tracey Calvert-Joshua for insight into the protein topology prediction programs. lvarez E, DeDiego ML, Nieto-Torres JL, Jimnez-Guardeo JM, Marcos-Villar L, Enjuanes L. The envelope protein of severe acute respiratory syndrome coronavirus interacts with the non-structural protein 3 and is ubiquitinated. J Virol. He M, Jenkins P, Bennett V. Cysteine 70 of ankyrin-G is S-palmitoylated and is required for function of ankyrin-G in membrane domain assembly. Ultrastructure and origin of membrane vesicles associated with the severe acute respiratory syndrome coronavirus replication complex. 2013;87(18):997382. J Am Chem Soc. Zumla A, Chan JF, Azhar EI, Hui DS, Yuen K-Y. Linkage of myristic acid (C14:0) to the N-terminal of a glycine residue found on some viral, cellular, or bacterial proteins, is known as N-terminal myristoylation [120,121,122,123]. Viruses have a protein coat called capsid, that encloses their genetic material. 1992;267(20):14094101. Of the CoV E proteins, only IBV, SARS-CoV, and MHV have been found to be palmitoylated [73, 93, 117]. They can infect humans, plants, animals, bacteria and fungi. Majeau N, Fromentin R, Savard C, Duval M, Tremblay MJ, Leclerc D. Palmitoylation of hepatitis C virus core protein is important for virion production. Nal B, Chan C, Kien F, Siu L, Tse J, Chu K, et al. 1996;15(8):20208. Severe acute respiratory syndrome coronavirus E protein transports calcium ions and activates the NLRP3 inflammasome. J Cell Biol. Diseases. The small envelope protein E is not essential for murine coronavirus replication. 2010;21(22):383852. Saha A, Murakami M, Kumar P, Bajaj B, Sims K, Robertson ES. 2006;78(7):93849. Nature. Basu J. EMBO J. 1985;37:20312. 2005;21(11):26516. PubMed Burtram C. Fielding. J Virol. 2013;29:55169. This review aims to establish the current knowledge on CoV E by highlighting the recent progress that has been made and comparing it to previous knowledge. Viruses are small germs (pathogens) that can infect you and make you sick. PLoS One. Surya W, Sams M, Torres J. PubMedGoogle Scholar. This suggests that there might, in fact, be a physical interaction between E and N but the reason and exact requirements for this interaction remains to be determined. The coronaviral genome encodes four major structural proteins: the spike (S) protein, nucleocapsid (N) protein, membrane (M) protein, and the envelope (E) protein, all of which are required to produce a structurally complete viral particle [29, 37, 38]. 1988;62(8):258795. Synthetic peptides corresponding to the full-length SARS-CoV E viroporin have also recently been shown to be capable of transporting Ca2+ and was linked to the inflammatory response often observed in ARDS [221]. 2004;318(4):8338. Correspondence to J Virol. However, this was found not to be the case, likely due to the proximity of the residue to the membrane [133]. J Virol. Respiratory syncytial virus uses a Vps4-independent budding mechanism controlled by Rab11-FIP2. Drug Discov Today. General Properties of Viruses Replication Cycle Summary EducationalObjectives General 1. Conversely, mutant V25F reverted to mutants with amino acid substitutions at either the same position (F25D) or positions relatively close to the original mutation (L19A, F20 L, F26 L, L27S, T30I, L37R). Autophagy is a cellular process that recycles excess or damaged cellular material to maintain the energy levels of the cell and ensure its survival. The authors proposed that the change in pH could be attributed to an interaction between the monomeric form of E and a host protein. The importance of these domains is evident by the drastic reduction of VLPs upon deletion of the domains [56]. Findings can only be more conclusive when supported by results from studies in more biologically relevant systems. By increasing the protein content, folding, and processing of the ER, viral infections can also trigger the UPR and this pathway can be used by the host cell as an antiviral response [231]. A closer look at the predicted PBM motif for each of the coronaviral genera , , and reveals that the PBM motif appears to be conserved only among the and CoVs and is not found in the CoVs (Fig. Westerbeck JW, Machamer CE. Ito M, Yanagi Y, Ichinohe T. Encephalomyocarditis virus viroporin 2B activates NLRP3 inflammasome. 2013;81(1):13647. The intracellular dynamic of protein palmitoylation. J Mol Biol. Some viruses have an external membrane envelope. J Virol. 2004;78(24):140437. Biochemistry. Hyser JM, Estes MK. The position of the palmitoylated cysteine residues in relation to the hydrophobic TMD likely increases the regions affinity for the membrane, serving to alter or stabilise association between the protein and the membrane. In fact, various recombinant CoVs (rCoVs) lacking the E gene (E) exhibit a strikingly aberrant morphology. Do viruses have protein coats? Coronaviruses are unique among enveloped viruses in that assembly of the viral envelope occurs at the ERGIC. Trends Microbiol. 2009;6(4):36780. The S glycoprotein plays . Hofmann K. TMbase-A database of membrane spanning proteins segments. Bioinformatics. Granted, the therapeutic application of stapled peptides, particularly regarding viral infections, is still relatively new, but their numerous advantages give them tremendous potential as antiviral agents. The anti-apoptotic protein B-cell lymphoma-extra-large (Bcl-xL) protein was the first host protein reported to interact with SARS-CoV E protein, alluding to the possibility that the coronaviral E protein is also capable of host-viral PPI [87]. Agirre A, Barco A, Carrasco L, Nieva JL. General Properties of Viruses - A.T. Still University Beale R, Wise H, Stuart A, Ravenhill BJ, Digard P, Randow F. A LC3-interacting motif in the influenza a virus M2 protein is required to subvert autophagy and maintain virion stability. Coronavirus diversity, phylogeny and interspecies jumping. In . Song HC, Seo M-Y, Stadler K, Yoo BJ, Choo Q-L, Coates SR, et al. Emerg Infect Dis. The ability of CoV E to assemble into homopentameric structures is clearly important in the formation of a functional CoV E viroporin [75, 76, 135,136,137,138, 140]. SARS associated coronavirus has a recombinant polymerase and coronaviruses have a history of host-shifting. Mechanistic understanding of N-glycosylation in Ebola virus glycoprotein maturation and function. J Virol. Google Scholar. The interaction between the cytoplasmic tails of the M and E proteins drives VLP production, suggesting that E participates in (1) viral assembly [56, 61, 89]. The ER can sustain a high load of protein content without being overwhelmed [228]. Yuan X, Wu J, Shan Y, Yao Z, Dong B, Chen B, et al. The coronaviral envelope consists predominantly of M while only a small portion of E is incorporated into the viral envelope of virions [100, 167, 168]. Although possible, only a very small number of host proteins have been shown to interact with CoV E. The monomeric and oligomeric forms were produced by transfection of mutated IBV E A26 to F26 (EA26F) and T16 to A16 (ET16A), respectively. 2013;1828(9):202631. 2000;18(1):861926. Recombinant respiratory syncytial virus bearing a deletion of either the NS2 or SH gene is attenuated in chimpanzees. Like other coronaviruses, the SARS-CoV-2 genome encodes spike (S) glycoproteins, which protrude from the surface of mature virions. J Virol. Regarding CoVs, replication of TGEV is negatively regulated by autophagy [279]. 1998;72(11):863643. However, the untagged E protein exhibited the topological conformation of a single transmembrane-spanning protein, demonstrating that the topology may be altered by the presence of the N-terminal tag [66]. Nevertheless, the main reason likely stems from differences in the features unique to each algorithm, such as, whether the algorithm would include multiple features of the target protein(s) or only a clearly defined set of criteria; how accurately the algorithm should discriminate between the different features; the point at which the specificity or sensitivity for a certain feature is defined as too broad or too narrow [102]. Host IQGAP1 and Ebola virus VP40 interactions facilitate virus-like particle egress. Guo L, Yu H, Gu W, Luo X, Li R, Zhang J, et al. In the absence of scission machinery, the budding process begins but ultimately stops, and render budding virions attached to the membrane by a small membranous neck. They explored the possibility of a targeting signal located in the luminal N-terminus but found the truncated terminus to be transported to the cell surface. By infecting mice with recombinant SARS-CoV viruses, they demonstrated that E caused syntenin to be redistributed to the cytoplasm where it triggered an overexpression of inflammatory cytokines. 2014;10(5):e1004077. 2005;102(39):140405. This is the only study so far to have shown that the E viroporin of any CoV is capable of Ca2+ transport. Hsieh P-K, Chang SC, Huang C-C, Lee T-T, Hsiao C-W, Kou Y-H, et al. Only two studies have reported a possible interaction between E and N, one for murine MHV and the other for SARS-CoV. It has even been proposed that the DMVs formed in CoV-infected cells might be the result of autophagy and derived from the rough ER [281]. 2015;478:7585. Viroporin formation appears to be mediated by ionic interactions rather than disulphide bonds as mutation of the porcine reproductive and respiratory syndrome virus (PRRSV) E protein cysteine residues appears to be dispensable for oligomerisation [219]. Virus glycosylation: role in virulence and immune interactions. Lim K, Liu D. The missing link in coronavirus assembly: retention of the avian coronavirus infectious bronchitis virus envelope protein in the pre-Golgi compartments and physical interaction between the envelope and membrane proteins. The study also shows that CoV E has an anti-apoptotic function in infected cells by suppressing the UPR during infection, likely as a survival mechanism and to continue viral propagation. The viral envelope is made up of a lipid bilayer embedded with viral proteins, including viral glycoproteins. The human polyoma JC virus agnoprotein acts as a viroporin. 2017;8(8):1268694. Bacteriophages replicate only in the cytoplasm, since prokaryotic cells do not have a nucleus or organelles. Ubiquitination and its counterpart, deubiquitination, are well-characterised post-translational modifications with that serve to maintain homeostasis through the regulation of cellular protein levels and their functions [128]. Elofsson A. Heijne Gv. Based on the hydropathy plot of the protein, the authors suggested that it might be buried inside the lipid bilayer [71]. Gonzalez ME, Carrasco L. Viroporins. Krogh A, Larsson B, Von Heijne G, Sonnhammer EL. Although S was shown to co-purify with E, the authors did not pursue the mechanism or importance of this interaction. Coronavirus envelope protein: current knowledge - Virology Journal They can also infect humans and cause disease to varying degrees, from upper respiratory tract infections (URTIs) resembling the common cold, to lower respiratory tract infections (LRTIs) such as bronchitis, pneumonia, and even severe acute respiratory syndrome (SARS) [5,6,7,8,9,10,11,12,13,14]. Respiratory syncytial virus inhibits lung epithelial Na+ channels by up-regulating inducible nitric-oxide synthase. Virology. J Virol. Influenza virus M2 protein mediates ESCRT-independent membrane scission. Very few studies have looked at the role of CoV E in the ER stress response and its ability to induce apoptosis. The PDZ-binding motif of severe acute respiratory syndrome coronavirus envelope protein is a determinant of viral pathogenesis.