SARS Virus Papain-Like Protease: A Mysterious Weapon
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Abstract
Introduction: Papain-like protease (PLpro) of SARS-CoV in association with 3Chemotrypsin-like protease (3CLpro or Mpro) are two proteases which auto-proteolyze replicase polyproteins pp1a/pp1ab. These poly-proteins are translated from ORF1a/ORF1b of the virus genome. Cleavage of pp1a/pp1ab releases non-structural proteins of the virus which orchestrate viral replication. In addition, PLpro as a deubiquitinase and deISGylase modifies the proteins involved in recognition of the virus by the sensors of host cell innate immunity system. In this manner, the virus reforms the ubiquitination and ISGylation of the cell proteins to progress its own replication without any interference from host cell restrictive strategies against the viruses. Furthermore, PLpro blocks IRF3 activation independent of deubiquinating processes. Besides, PLpro induces pulmonary fibrosis through pathways involving ROS and MAPK.
Conclusion: Inhibition of PLpro allows innate immunity to sense and react against the invasion of SARS-CoV and to activate IRF3 to induce type I IFN expression. Thenceforth, proper development and signaling of innate immunity result in a long-term efficient cell/humoral adaptive immunity. Moreover, suppression of PLpro prevents cleavage of nsp3 and hence replication of the virus and through abolishing ubiquitin-proteasome/MAPK/ERK- and ROS/MAPK-mediated pathways prevent pulmonary fibrosis.
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38.Frieman, M., et al., Severe acute respiratory syndrome coronavirus papain-like protease ubiquitin-like domain and catalytic domain regulate antagonism of IRF3 and NF-κB signaling. Journal of virology, 2009. 83(13): p. 6689-6705.
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41.Li, S.-W., et al., SARS coronavirus papain-like protease induces Egr-1-dependent up-regulation of TGF-β1 via ROS/p38 MAPK/STAT3 pathway. Scientific reports, 2016. 6: p. 25754.
42.Li, S.W., et al., Correlation between TGF‐β1 expression and proteomic profiling induced by severe acute respiratory syndrome coronavirus papain‐like protease. Proteomics, 2012. 12(21): p. 3193-3205.
2.Phan, M.V., et al., Identification and characterization of Coronaviridae genomes from Vietnamese bats and rats based on conserved protein domains. Virus evolution, 2018. 4(2): p. vey035.
3.Fehr, A.R. and S. Perlman, Coronaviruses: An overview of their replication and pathogenesis. Methods in Molecular Biology, 2015. 1282.
4.Walker, P.J., et al., Changes to virus taxonomy and the International Code of Virus Classification and Nomenclature ratified by the International Committee on Taxonomy of Viruses (2019). Archives of virology, 2019. 164(9): p. 2417-2429.
5.Cui, J., F. Li, and Z.-L. Shi, Origin and evolution of pathogenic coronaviruses. Nature reviews Microbiology, 2019. 17(3): p. 181-192.
6.Coleman, C.M. and M.B. Frieman, Coronaviruses: important emerging human pathogens. Journal of virology, 2014. 88(10): p. 5209-5212.
7.Organization, W.H., Consensus document on the epidemiology of severe acute respiratory syndrome (SARS). 2003, World Health Organization.
8.Masters, P.S., The molecular biology of coronaviruses. Advances in virus research, 2006. 66: p. 193-292.
9.Gorbalenya, A.E., et al., Nidovirales: evolving the largest RNA virus genome. Virus research, 2006. 117(1): p. 17-37.
10.Báez-Santos, Y.M., S.E.S. John, and A.D. Mesecar, The SARS-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds. Antiviral research, 2015. 115: p. 21-38.
11.Couso, J.-P. and P. Patraquim, Classification and function of small open reading frames. Nature reviews Molecular cell biology, 2017. 18(9): p. 575-589.
12.Snijder, E., E. Decroly, and J. Ziebuhr, The nonstructural proteins directing coronavirus RNA synthesis and processing, in Advances in virus research. 2016, Elsevier. p. 59-126.
13.Xu, X., et al., Molecular model of SARS coronavirus polymerase: implications for biochemical functions and drug design. Nucleic acids research, 2003. 31(24): p. 7117-7130.
14.Fung, T.S. and D.X. Liu, Post-translational modifications of coronavirus proteins: roles and function. Future Virology, 2018. 13(6): p. 405-430.
15.Harcourt, B.H., et al., Identification of severe acute respiratory syndrome coronavirus replicase products and characterization of papain-like protease activity. Journal of virology, 2004. 78(24): p. 13600-13612.
16.Lei, J., Y. Kusov, and R. Hilgenfeld, Nsp3 of coronaviruses: Structures and functions of a large multi-domain protein. Antiviral research, 2018. 149: p. 58-74.
17.Oostra, M., et al., Topology and membrane anchoring of the coronavirus replication complex: not all hydrophobic domains of nsp3 and nsp6 are membrane spanning. Journal of virology, 2008. 82(24): p. 12392-12405.
18.Angelini, M.M., et al., Severe acute respiratory syndrome coronavirus nonstructural proteins 3, 4, and 6 induce double-membrane vesicles. MBio, 2013. 4(4).
19.Serrano, P., et al., Nuclear magnetic resonance structure of the N-terminal domain of nonstructural protein 3 from the severe acute respiratory syndrome coronavirus. Journal of virology, 2007. 81(21): p. 12049-12060.
20.Fehr, A.R., et al., The nsp3 macrodomain promotes virulence in mice with coronavirus-induced encephalitis. Journal of virology, 2015. 89(3): p. 1523-1536.
21.Imbert, I., et al., The SARS-Coronavirus PLnc domain of nsp3 as a replication/transcription scaffolding protein. Virus research, 2008. 133(2): p. 136-148.
22.Barretto, N., et al., The papain-like protease of severe acute respiratory syndrome coronavirus has deubiquitinating activity. Journal of virology, 2005. 79(24): p. 15189-15198.
23.Lee, H., et al., Synergistic Inhibitor Binding to the Papain-Like Protease of Human SARS Coronavirus–Mechanistic and Inhibitor Design Implications. ChemMedChem, 2013. 8(8): p. 1361.
24.Lindner, H.A., et al., Selectivity in ISG15 and ubiquitin recognition by the SARS coronavirus papain-like protease. Archives of biochemistry and biophysics, 2007. 466(1): p. 8-14.
25.Rajagopalan, K., et al., A majority of the cancer/testis antigens are intrinsically disordered proteins. Journal of cellular biochemistry, 2011. 112(11): p. 3256-3267.
26.Pinto-Fernández, A., et al., Comprehensive landscape of active deubiquitinating enzymes profiled by advanced chemoproteomics. Frontiers in chemistry, 2019. 7: p. 592.
27.Kravtsova-Ivantsiv, Y. and A. Ciechanover, Non-canonical ubiquitin-based signals for proteasomal degradation. Journal of cell science, 2012. 125(3): p. 539-548.
28.Rajsbaum, R. and A. García-Sastre, Viral evasion mechanisms of early antiviral responses involving regulation of ubiquitin pathways. Trends in microbiology, 2013. 21(8): p. 421-429.
29.Randles, L. and K.J. Walters, Ubiquitin and its binding domains. Frontiers in bioscience (Landmark edition), 2012. 17: p. 2140.
30.Ohtake, F., et al., The K48-K63 branched ubiquitin chain regulates NF-κB signaling. Molecular cell, 2016. 64(2): p. 251-266.
31.Thompson, M.R., et al., Pattern recognition receptors and the innate immune response to viral infection. Viruses, 2011. 3(6): p. 920-940.
32.Zhang, D. and D.-E. Zhang, Interferon-stimulated gene 15 and the protein ISGylation system. Journal of interferon & cytokine research, 2011. 31(1): p. 119-130.
33.Lee, H.-C., K. Chathuranga, and J.-S. Lee, Intracellular sensing of viral genomes and viral evasion. Experimental & molecular medicine, 2019. 51(12): p. 1-13.
34.Lindner, H.A., et al., The papain-like protease from the severe acute respiratory syndrome coronavirus is a deubiquitinating enzyme. Journal of virology, 2005. 79(24): p. 15199-15208.
35.Ratia, K., et al., Severe acute respiratory syndrome coronavirus papain-like protease: structure of a viral deubiquitinating enzyme. Proceedings of the National Academy of Sciences, 2006. 103(15): p. 5717-5722.
36.Ratia, K., et al., A noncovalent class of papain-like protease/deubiquitinase inhibitors blocks SARS virus replication. Proceedings of the National Academy of Sciences, 2008. 105(42): p. 16119-16124.
37.Matthews, K., et al., The SARS coronavirus papain like protease can inhibit IRF3 at a post activation step that requires deubiquitination activity. Virology journal, 2014. 11(1): p. 209.
38.Frieman, M., et al., Severe acute respiratory syndrome coronavirus papain-like protease ubiquitin-like domain and catalytic domain regulate antagonism of IRF3 and NF-κB signaling. Journal of virology, 2009. 83(13): p. 6689-6705.
39.Niemeyer, D., et al., The papain-like protease determines a virulence trait that varies among members of the SARS-coronavirus species. PLoS pathogens, 2018. 14(9): p. e1007296.
40.Ghosh, A.K., et al., Severe acute respiratory syndrome coronavirus papain-like novel protease inhibitors: design, synthesis, protein− ligand X-ray structure and biological evaluation. Journal of medicinal chemistry, 2010. 53(13): p. 4968-4979.
41.Li, S.-W., et al., SARS coronavirus papain-like protease induces Egr-1-dependent up-regulation of TGF-β1 via ROS/p38 MAPK/STAT3 pathway. Scientific reports, 2016. 6: p. 25754.
42.Li, S.W., et al., Correlation between TGF‐β1 expression and proteomic profiling induced by severe acute respiratory syndrome coronavirus papain‐like protease. Proteomics, 2012. 12(21): p. 3193-3205.
| Files | ||
| Issue | Vol 5 No 4 (2019) | |
| Section | Review Article(s) | |
| DOI | https://doi.org/10.18502/jbe.v5i4.3873 | |
| Keywords | ||
| Papain-like protease; Ubiquitination Interferon stimulated gene 15 (ISG15) Deubiquitination SARS coronavirus (SARS-CoV) Middle East respiratory syndrome coronavirus (MERS-CoV) Pulmonary Fibrosis | ||
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How to Cite
1.
Nejat R, Sadr AS. SARS Virus Papain-Like Protease: A Mysterious Weapon. JBE. 2020;5(4):321-328.
