Nucleocapsid protein of SARS-CoV activates interleukin-6 expression through cellular transcription factor NF-κB
Open accessAbstract
High levels of interleukin-6 (IL-6) in the acute stage associated with lung lesions were found in SARS patients. To evaluate the mechanisms behind this event, we investigated the roles of SARS-CoV proteins in the regulation of IL-6. Results showed that the viral nucleocapsid (N) protein activated IL-6 expression in a concentration-dependent manner. Promoter analyses suggested that NF-kappaB binding element was required for IL-6 expression regulated by N protein. Further studies demonstrated that N protein bound directly to NF-kappaB element on the promoter. We also showed that N protein activated IL-6 expression through NF-kappaB by facilitating the translocation of NF-kappaB from cytosol to nucleus. Mutational analyses revealed that two regions of N protein were essential for its function in the activation of IL-6. These results provided new insights into understanding the mechanism involved in the function of SARS-CoV N protein and pathogenesis of the virus.
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The nucleocapsid protein of SARS-CoV-1 activates IL-6 expression through NF-κB by facilitating the translocation of NF-κB from the cytosol to the nucleus.
“In addition to this PRR-mediated activation of NF-κB, the nucleocapsid protein of SARS-CoV-1 activates IL-6 expression through NF-κB by facilitating the translocation of NF-κB from the cytosol to the nucleus (341).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [341]
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“The biological functions of coronavirus N protein are thought to participate in the replication and transcription of viral RNA and to interfere with the cell cycle of host cells (Parker and Masters, 1990; Kuo and Masters, 2002).”
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Activation of NF-κB by the Full-length Nucleocapsid Protein of the SARS Coronavirus
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“Nucleocapsid protein of SARS-CoV activates the expression of IL-6 It has been shown that high serum levels of IL-6 in the acute stage associated with lung lesions were found in SARS patients (Hsueh et al., 2004).”
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“AY394850) were amplified by RT-PCR from RNA isolated previously from SARSCoV infected Vero E6 cells (Zhu et al., 2005) using corresponding primers listed in Table 2.”
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“The N proteins of many coronaviruses are highly immunogenic and abundantly expressed during infection (Liu et al., 2001; Narayanan et al., 2003) .”
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“In addition to this PRR-mediated activation of NF-κ B, the nucleo-capsid protein of SARS-CoV-1 activates IL-6 expression through NF-κ B by facilitating the translocation of NF-κ B from the cytosol to the nucleus (341).”
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“…IRF-3 phosphorylation Lu et al. (2011), Kopecky-Bromberg et al. (2007) Activates NF- B and upregulates the expression of IL-6 Liao et al. (2005), Zhang et al. (2007) Activates AP-1 He et al. (2003) Induces the expression of IL8 via AP-1 activation Chang et al. (2004) 3a SARS-CoV Downregulates…”
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“The viral nucleocapsid protein of SARS-CoV can also bind the NF-kB regulatory element on the IL-6 promoter, and activity is highest when the p65 subunit is present (Zhang et al., 2007).”
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“Finally, the N protein of SARS-CoV-2 induces the expression of IL-6 in infected airway epithelium by binding to the NF-κB regulatory elements of the IL-6 promoter (82).”
BackgroundThe four horsemen of a viral Apocalypse: The pathogenesis of SARS-CoV-2 infection (COVID-19)
Domingo, P., Mur, I., Pomar, V., Corominas, H., Casademont, J., & Benito, N. (2020) · EBioMedicine · doi:10.1016/j.ebiom.2020.102887 · Cited by 168 · see citing works
Magro, G. (2020) · Virus Research · doi:10.1016/j.virusres.2020.198070 · Cited by 130 · see citing works
“Interestingly, among all SARS-CoV-1 structural proteins (N, S, E and M), the nucleocapsid protein (N) significantly induced the activation of IL-6 promotor in human airway epithelial cell cultures (Zhang et al., 2007).”
BackgroundCOVID19: an announced pandemic
Platto, S., Xue, T., & Carafoli, E. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-02995-9 · Cited by 124 · see citing works
Hotez, P. J., Bottazzi, M. E., & Corry, D. B. (2020) · Microbes and Infection · doi:10.1016/j.micinf.2020.04.005 · Cited by 114 · see citing works
“There is additional evidence to suggest the SARS N protein is a potent inducer of IL-6 responses, and may mediate coronavirus lung pathology (9) .”
BackgroundPoppe, M., Wittig, S., Jurida, L., Bartkuhn, M., Wilhelm, J., Müller, H., Beuerlein, K., Karl, N., Bhuju, S., Ziebuhr, J., et al. (2017) · PLoS Pathogens · doi:10.1371/journal.ppat.1006286 · Cited by 98 · see citing works
Potential neurological impact of coronaviruses: implications for the novel SARS-CoV-2
Iroegbu, J. D., Ifenatuoha, C. W., & Ijomone, O. M. (2020) · Neurological Sciences · doi:10.1007/s10072-020-04469-4 · Cited by 90 · see citing works
Battagello, D. S., Dragunas, G., Klein, M., Ayub, A. L. P., Velloso, F. J., & Correa, R. G. (2020) · Clinical Science · doi:10.1042/cs20200904 · Cited by 87 · see citing works
Antiviral activities of mycophenolic acid and IMD‐0354 against SARS‐CoV‐2
Kato, F., Matsuyama, S., Kawase, M., Hishiki, T., Katoh, H., & Takeda, M. (2020) · Microbiology and Immunology · doi:10.1111/1348-0421.12828 · Cited by 81 · see citing works
Boosted expression of the SARS-CoV nucleocapsid protein in tobacco and its immunogenicity in mice
Zheng, N., Xia, R., Yang, C., Yin, B., Yin, L., Duan, C., Liang, L., Guo, H., & Xie, Q. (2009) · Vaccine · doi:10.1016/j.vaccine.2009.05.073 · Cited by 80 · see citing works
“The induction of IFN-␥ [25, 28, 29] , IL-6 [37] , IL-11 [38] and other cytokines was also observed to related with SARS-N protein.”
BackgroundHuman Coronavirus OC43 Nucleocapsid Protein Binds MicroRNA 9 and Potentiates NF-κB Activation
Lai, F. W., Stephenson, K. B., Mahony, J. B., & Lichty, B. D. (2013) · Journal of Virology · doi:10.1128/jvi.02678-13 · Cited by 73 · see citing works
Glutathione Supplementation as an Adjunctive Therapy in COVID-19
Guloyan, V., Oganesian, B., Baghdasaryan, N., Yeh, C., Singh, M., Guilford, F. T., Ting, Y.-S., & Venketaraman, V. (2020) · Antioxidants · doi:10.3390/antiox9100914 · Cited by 73 · see citing works
“It has been shown that SARS-CoV-1 N protein interacts with the host transcriptional factor NF-κB in a dose-dependent manner to regulate IL-6 expression [55,56].”
Backgroundde Wilde, A. H., Wannee, K. F., Scholte, F. E. M., Goeman, J. J., ten Dijke, P., Snijder, E. J., Kikkert, M., & van Hemert, M. J. (2015) · Journal of Virology · doi:10.1128/jvi.01029-15 · Cited by 72 · see citing works
“tory cytokine IL-8 (62), and IL-6 and IL-8 levels were elevated in the serum of SARS-CoV-infected patients (62, 63).”
BackgroundProper Management of People with Obesity during the COVID-19 Pandemic
Lim, S. K., Shin, S. M., Nam, G. E., Jung, C. H., & Koo, B. K. (2020) · Journal of Obesity & Metabolic Syndrome · doi:10.7570/jomes20056 · Cited by 71 · see citing works
Karwaciak, I., Sałkowska, A., Karaś, K., Dastych, J., & Ratajewski, M. (2021) · Vaccines · doi:10.3390/vaccines9010054 · Cited by 68 · see citing works
Wang, Z., Li, K., Maskey, A., Huang, W., Toutov, A. A., Yang, N., Srivastava, K. D., Geliebter, J., Tiwari, R. K., Miao, M., et al. (2021) · The FASEB Journal · doi:10.1096/fj.202001792r · Cited by 66 · see citing works
Beta‐Adrenergic Blockers as a Potential Treatment for COVID‐19 Patients
Vasanthakumar, N. (2020) · BioEssays · doi:10.1002/bies.202000094 · Cited by 63 · see citing works
“[19] Since the nucleocapsid protein of SARS-CoV-2 shares 89.”
BackgroundFiorino, S., Gallo, C. G., Zippi, M., Sabbatani, S., Manfredi, R., Moretti, R., Fogacci, E., Maggioli, C., Loffredo, F. T., Giampieri, E., et al. (2020) · Aging Clinical and Experimental Research · doi:10.1007/s40520-020-01669-y · Cited by 60 · see citing works
Viruses with Single-Stranded, Positive-Sense RNA Genomes
Modrow, S., Falke, D., Truyen, U., & Schätzl, H. M. (2013) · Springer eBooks · doi:10.1007/978-3-642-20718-1_14 · Cited by 60 · see citing works
Leija-Martínez, J. J., Huang, F.-Y., Del-Río-Navarro, B., Sánchez-Muñoz, F., Muñoz-Hernández, O., Giacoman-Martínez, A., Hall-Mondragon, M. S., & Espinosa-Velazquez, D. (2020) · Medical Hypotheses · doi:10.1016/j.mehy.2020.109935 · Cited by 54 · see citing works
Vallée, A., Lecarpentier, Y., & Vallée, J.-N. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.666693 · Cited by 58 · see citing works
“SARS-CoV infection leads to a release of proinflammatory cytokines and growth factors to activate the IkB Kinase (IKK), which phosphorylates and degrades the IkB protein through an ubiquitination mechanism (28).”
BackgroundDulek, D. E., Fuhlbrigge, R. C., Tribble, A. C., Connelly, J. A., Loi, M. M., Chebib, H. E., Chandrakasan, S., Otto, W. R., Diorio, C. J., Keim, G. P., et al. (2020) · Journal of the Pediatric Infectious Diseases Society · doi:10.1093/jpids/piaa098 · Cited by 55 · see citing works
“production of IL-6 and TNF-; similar results were also observed with purified coronavirus spike (S) or nucleocapsid (N) proteins [70, 71].”
ResultDing, Z., An, K., Xie, L., Wu, W., Zhang, R., Wang, D., Fang, Y., Chen, H., Xiao, S., & Fang, L. (2017) · Virology · doi:10.1016/j.virol.2017.04.024 · Cited by 54 · see citing works
“Regarding other coronavirus, the SARS-CoV N protein activates IL-6 expression through NF-κB by facilitating the translocation of NF-κB from the cytosol to the nucleus or by binding directly to the NF-κB element on the promoter (Zhang et al., 2007).”
BackgroundSelf-citationEvans, R. M., & Lippman, S. M. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.09.007 · Cited by 49 · see citing works
Diemer, C., Schneider, M., Seebach, J., Quaas, J., Frösner, G., Schätzl, H. M., & Gilch, S. (2007) · Journal of Molecular Biology · doi:10.1016/j.jmb.2007.11.081 · Cited by 48 · see citing works
“24 One unique feature of SARS-CoV N is the presence of a lysine-rich stretch near the C-terminus of the protein, which might enable its nuclear localization. 4 Furthermore, two additional putative nuclear localization signals (NLSs) within N have been suggested, with one located at the N-terminal and the other at the…”
BackgroundChen, L., Guan, W., Qiu, Z.-E., Xu, J.-B., Bai, X., Hou, X.-C., Sun, J., Qu, S., Huang, Z.-X., Lei, T.-L., et al. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01048-1 · Cited by 46 · see citing works
“These findings were consistent with the previously reported associations between SARS-CoV N protein stimulation and NF-κB-mediated inflammatory responses.(43) The accumulation of intracellular Cl induced by coronavirus N proteins might be a phenomenon generalizable to the sarbecoviruses.”
ResultSelf-citationProinflammatory Cytokines in Chronic Respiratory Diseases and Their Management
Chavda, V. P., Bezbaruah, R., Ahmed, N., Alom, S., Bhattacharjee, B., Nalla, L. V., Rynjah, D., Gadanec, L. K., & Apostolopoulos, V. (2025) · Cells · doi:10.3390/cells14060400 · Cited by 46 · see citing works
“Viral proteins have been shown to trigger the release of IL-6, which activates the transcription factor NF-κ B [100].”
Rana, A. K., Rahmatkar, S. N., Kumar, A., & Singh, D. (2020) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2020.08.002 · Cited by 47 · see citing works
“A study suggested that the nucleocapsid protein of SARS-CoV directly interacts with NF-κB, translocate it to the nucleus, and finally upregulates IL-6 gene expression [37].”
Amini‐Farsani, Z., Yadollahi‐Farsani, M., Arab, S., Forouzanfar, F., Yadollahi, M., & Asgharzade, S. (2021) · International Immunopharmacology · doi:10.1016/j.intimp.2021.108071 · Cited by 45 · see citing works
Tang, B., Zhao, R., Sun, Y., Zhu, Y., Zhong, J. S., Zhao, G., & Zhu, N. (2011) · Molecular Immunology · doi:10.1016/j.molimm.2011.01.003 · Cited by 44 · see citing works
“…expression has been studied extensively, and it is now well accepted that IL-6 expression is regulated by TLR pathway and controlled by several transcription factors such as NF- B, C/EBP, AP-1 and SP-1 (Carlotti et al., 2000; Merola et al., 1996; Vanden Berghe et al., 2000; Zhang et al., 2007).”
BackgroundSelf-citationPagliari, F., Marafioti, M. G., Genard, G. C., Candeloro, P., Viglietto, G., Seco, J. C., & Tirinato, L. (2020) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2020.578964 · Cited by 43 · see citing works
“These findings suggest that NF-κB induction and its signaling might be cell context-specific and may influence distinct aspects of immune function (KopeckyBromberg et al., 2007; Zhang et al., 2007).”
BackgroundPeng, N., Liu, S., Xia, Z., Ren, S., Feng, J. J., Jing, M.-Z., Gao, X., Wiemer, E. A. C., & Zhu, Y. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1501481 · Cited by 42 · see citing works
Self-citationMesodynamics in the SARS nucleocapsid measured by NMR field cycling
Clarkson, M. W., Lei, M., Eisenmesser, E. Z., Labeikovsky, W., Redfield, A. G., & Kern, D. (2009) · Journal of Biomolecular NMR · doi:10.1007/s10858-009-9347-6 · Cited by 39 · see citing works
“…Redfield (&) Department of Biochemistry, MS009 Brandeis University, Waltham, MA 02452, USA e-mail: redfield@brandeis.edu et al. 2007), capsid assembly (Hsieh et al. 2005; Saikatendu et al. 2007), cell-cycle disruption (Surjit et al. 2006), and immune response to the SARS virus (Zhang et al. 2007).”
BackgroundMethodInfluentialBeaudoin, C. A., Jamasb, A. R., Alsulami, A. F., Copoiu, L., van Tonder, A. J., Hala, S. M., Bannerman, B. P., Thomas, S. E., Vedithi, S. C., Torres, P. H. M., et al. (2021) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2021.06.041 · Cited by 36 · see citing works
“However, several alternative theories have been proposed to explain the increases in IL-6 during severe infection; for example, the SARS-CoV nucleocapsid protein has been shown to activate IL-6 expression [79].”
Xia, L., Huang, W., Wu, J., Yang, Y., Zhang, Q., Zhou, Z., Zhu, H., Lei, P., Shen, G., & Tian, D. (2009) · Virology · doi:10.1016/j.virol.2008.11.042 · Cited by 37 · see citing works
“To determine the roles of NF-κB in the HBx-induced activation of MIG promoter, pCMV-HBx and (−983/+33)MIG were co-transfected intoHepG2 cells and then the cellswere treatedwithMG-132 (anNF-κB inhibitor) at different concentrations (Zhang et al., 2007).”
BackgroundSelf-citationFrom Influenza Virus to Novel Corona Virus (SARS-CoV-2)–The Contribution of Obesity
Bhattacharya, I., Ghayor, C., Domínguez, A. P., & Weber, F. E. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.556962 · Cited by 36 · see citing works
Fang, Y.-T., Lin, C., Liao, P., Kuo, Y., Wang, S., Yeh, T., Shieh, C.-C. K., Su, I., Lei, H.-Y., & Lin, Y.-S. (2009) · Molecular Immunology · doi:10.1016/j.molimm.2009.11.019 · Cited by 35 · see citing works
“Furthermore, a cytokine and chemokine storm has been demonstrated and its intensity associated with some clinical manifestations (Cameron et al., 2008; He et al., 2006; Huang et al., 2005; Jiang et al., 2005a; Wong et al., 2004; Zhang et al., 2007).”
BackgroundMilani, D., Caruso, L., Zauli, E., Owaifeer, A. M. A., Secchiero, P., Zauli, G., Gemmati, D., & Tisato, V. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.871583 · Cited by 34 · see citing works
Zhang, B., Tian, J., Zhang, Q., Xie, Y., Wang, K., Qiu, S., Lu, K., & Liu, Y. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.761173 · Cited by 32 · see citing works
“In vitro experiments have shown that the SARS-CoV N protein can directly interact with NF-κB, transport it to the nucleus, and ultimately upregulate IL-6 gene expression (Zhang et al., 2007).”
BackgroundPham, M. T., Yang, A. J., Kao, M., Gankhuyag, U., Zayabaatar, E., Jin, S.-L. C., & Huang, C.-M. (2021) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2021.108821 · Cited by 32 · see citing works
Qian, S., Gao, Z., Cao, R., Yang, K., Cui, Y., Li, S., Meng, X., He, Q., & Li, Z. (2020) · Frontiers in Microbiology · doi:10.3389/fmicb.2019.03085 · Cited by 29 · see citing works
“Both the SR-rich truncated proteins of the N protein of SARS coronavirus and PEDV can effectively promote the activation of the NF-κB signaling pathway (Zhang et al., 2007; Cao et al., 2015a) .”
BackgroundPourgholaminejad, A., Pahlavanneshan, S., & Basiri, M. (2021) · Scandinavian Journal of Immunology · doi:10.1111/sji.13131 · Cited by 31 · see citing works
SARS-CoV-2 and Multiple Sclerosis: Potential for Disease Exacerbation
MacDougall, M., Sleiman, J. E.-H., Beauchemin, P., & Rangachari, M. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.871276 · Cited by 29 · see citing works
Jamalkhah, M., Asaadi, Y., Azangou‐Khyavy, M., Khanali, J., Soleimani, M., Kiani, J., & Arefian, E. (2021) · Journal of Translational Medicine · doi:10.1186/s12967-021-02840-3 · Cited by 29 · see citing works
“It is activated in response to the virus elements, including N protein [119], and accumulating evidence is attributing the same feature to it in COVID-19 as well.”
BackgroundShalash, A. O., Hussein, W. M., Skwarczyński, M., & Tóth, I. (2021) · Advanced Science · doi:10.1002/advs.202100985 · Cited by 25 · see citing works
Arita, R., Ono, R., Saito, N., Takayama, S., Namiki, T., Ito, T., & Ishii, T. (2020) · Traditional & Kampo Medicine · doi:10.1002/tkm2.1258 · Cited by 26 · see citing works
“Moreover, the nucleocapsid protein of SARSCoV was reported to activate IL-6 expression [76].”
BackgroundAnti-nucleocapsid antibodies enhance the production of IL-6 induced by SARS-CoV-2 N protein
Nakayama, E. E., Kubota‐Koketsu, R., Sasaki, T., Suzuki, K., Uno, K., Shimizu, J., Okamoto, T., Matsumoto, H., Matsuura, H., Hashimoto, S., et al. (2022) · Scientific Reports · doi:10.1038/s41598-022-12252-y · Cited by 23 · see citing works
Farkhad, N. K., Reihani, H., Sedaghat, A., Moghadam, A. A., Moghaddam, A. B., & Tavakol‐Afshari, J. (2021) · Regenerative Therapy · doi:10.1016/j.reth.2021.05.007 · Cited by 22 · see citing works
“It has been proven that the viral nucleocapsid SARS-CoV N protein is responsible for the elevated IL-6 levels and lung injury in the severe stage of disease progression in SARS patients [42].”
The Potential Role of Cytokine Storm Pathway in the Clinical Course of Viral Respiratory Pandemic
Murdaca, G., Paladin, F., Tonacci, A., Isola, S., Allegra, A., & Gangemi, S. (2021) · Biomedicines · doi:10.3390/biomedicines9111688 · Cited by 26 · see citing works
“In SARS-Cov and MERS-Cov, increased IFN-γ levels have been associated with inflammation and extensive lung damage [45,46].”
BackgroundLin, Z., Gao, Q., Qian, F., Jinlian, M., Lishi, Z., Yu, Q., Tian, C., Zhenhua, C., Ping, W., & Lin, B. (2020) · SSRN Electronic Journal · doi:10.2139/ssrn.3561932 · Cited by 22 · see citing works
Hanafy, A. S., & Abd-Elsalam, S. M. (2020) · World Journal of Gastroenterology · doi:10.3748/wjg.v26.i46.7272 · Cited by 22 · see citing works
Categorizing Sequences of Concern by Function To Better Assess Mechanisms of Microbial Pathogenesis
Godbold, G. D., Kappell, A. D., LeSassier, D. S., Treangen, T. J., & Ternus, K. L. (2021) · Infection and Immunity · doi:10.1128/iai.00334-21 · Cited by 22 · see citing works
“Neisseria meningitidis (85), GRA24 from Toxoplasma gondii (86), VvpM from Vibrio vulnificus (87), and nucleocapsid protein (88, 89), spike glycoprotein (90, 91),”
BackgroundThe Role of the Nuclear Factor-Kappa B (NF-κB) Pathway in SARS-CoV-2 Infection
Kesika, P., Thangaleela, S., Sisubalan, N., Radha, A., Sivamaruthi, B. S., & Chaiyasut, C. (2024) · Pathogens · doi:10.3390/pathogens13020164 · Cited by 21 · see citing works
“The examination of viral gene expression features and evolutionary distinctions in SARS-CoV-2-infected cells from the BALF of patients experiencing moderate and severe COVID-19 was conducted using single-cell and bulk tissue transcriptome data.”
MethodThe Role of Obesity in the Immunopathogenesis of COVID-19 Respiratory Disease and Critical Illness
Kuperberg, S. J., & Navetta‐Modrov, B. (2021) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2020-0236tr · Cited by 21 · see citing works
“This may be especially pertinent because an animal model of SARS-CoV-1 (87) infection demonstrated that intranuclear IL-6 expression was activated via NF-kB, indicating the need for further study in SARS-CoV-2 with respect to B cell–induced transcriptional activity.”
Mu, Y., Yu, Y., Yue, X., Musarat, I., Gong, R., Zhu, C., Liu, Y., Liu, F., Zhu, Y., & Wu, J. (2011) · Virus Research · doi:10.1016/j.virusres.2011.01.001 · Cited by 19 · see citing works
Self-citationRecent clinical findings on the role of kinase inhibitors in COVID-19 management
Malekinejad, Z., Baghbanzadeh, A., Nakhlband, A., Baradaran, B., Jafari, S., Bagheri, Y., Raei, F., Montazersaheb, S., & Farahzadi, R. (2022) · Life Sciences · doi:10.1016/j.lfs.2022.120809 · Cited by 18 · see citing works
The Role of Glutathione in Prevention of COVID-19 Immunothrombosis: A Review
Glassman, I., Le, N., Mirhosseini, M., Alcantara, C. A., Asif, A., Goulding, A., Muneer, S., Singh, M., Robison, J., Guilford, F., et al. (2023) · Frontiers in Bioscience-Landmark · doi:10.31083/j.fbl2803059 · Cited by 18 · see citing works
Fiorino, S., Zippi, M., Gallo, C. G., Sifo, D., Sabbatani, S., Manfredi, R., Rasciti, E., Rasciti, L., Giampieri, E., Corazza, I., et al. (2020) · British Journal Of Nutrition · doi:10.1017/s0007114520002913 · Cited by 17 · see citing works
“In particular, nucleocapsid (N) and spike (S) SARS-CoV proteins possess direct binding sites on several specific DNA sequences, localised in the promoter region of a wide series of interleukins and cytokines(31,32).”
BackgroundAnwar, M. M., Badawi, A. M., & Eltablawy, N. A. (2020) · eNeurologicalSci · doi:10.1016/j.ensci.2020.100290 · Cited by 18 · see citing works
Karwaciak, I., Karaś, K., Sałkowska, A., Pastwińska, J., & Ratajewski, M. (2022) · Molecules · doi:10.3390/molecules27123651 · Cited by 15 · see citing works
Hepatitis C virus and host cell nuclear transport machinery: a clandestine affair
Bonamassa, B., Ciccarese, F., Antonio, V. D., Contarini, A., Palù, G., & Alvisi, G. (2015) · Frontiers in Microbiology · doi:10.3389/fmicb.2015.00619 · Cited by 17 · see citing works
“Strikingly, several proteins encoded by cytoplasmic-replicating viruses similarly interact with the nuclear transport apparatus, mainly with the aim to interfere with host cell functionality, promoting their self-propagation (Camus-Bouclainville et al., 2004; Zhang et al., 2007; Alvisi et al., 2008; Wang et al., 2012)…”
BackgroundMagro, G. (2020) · Travel Medicine and Infectious Disease · doi:10.1016/j.tmaid.2020.101685 · Cited by 17 · see citing works
Wei, W., Li, H.-C., Chen, C. Y., Yang, C.-H., Lee, S.-K., Wang, C., Ma, H.-C., Juang, Y., & Lo, S. (2012) · Archives of Virology · doi:10.1007/s00705-011-1221-7 · Cited by 17 · see citing works
Integrative Transcriptome Analyses Empower the Anti-COVID-19 Drug Arsenal
El-Hachem, N., Eid, E. S., Nemer, G. M., Dbaibo, G. S., Abbas, O. M., Rubeiz, N., Zeineldine, S. M., Matar, G. M., Bikorimana, J., Shammaa, R., et al. (2020) · iScience · doi:10.1016/j.isci.2020.101697 · Cited by 16 · see citing works
Kao, M., Yang, J., Balasubramaniam, A., Traisaeng, S., Yang, A. J., Yang, J. J., Salamon, B. P., Herr, D. R., & Huang, C. (2022) · Microbial Biotechnology · doi:10.1111/1751-7915.13994 · Cited by 16 · see citing works
“This result demonstrates for the first time that NPP of SARS-CoV-2 is sufficient to up-regulate IL-6 in the lung and supported the previous finding that NPP of other coronavirus can activate IL-6 gene expression by binding directly to NFjB regulatory element on IL-6 promoter (Zhang et al., 2007).”
BackgroundResultInfluentialThe controversial effect of smoking and nicotine in SARS-CoV-2 infection
Salehi, Z., Gh, B. F. N. M., Nourian, Y. H., Jamalkandi, S. A., & Ghanei, M. (2023) · Allergy Asthma and Clinical Immunology · doi:10.1186/s13223-023-00797-0 · Cited by 18 · see citing works
Gasparello, J., Marzaro, G., Papi, C., Gentili, V., Rizzo, R., Zurlo, M., Scapoli, C., Finotti, A., & Gambari, R. (2023) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2023.5279 · Cited by 17 · see citing works
“Since it has been reported that the SARS‑CoV N‑protein binds to the NF‑ κ B promoter, thereby stimulating the NF‑ κ B transcription (63), further investiga‑ tions were conducted to determine whether lower expression of the N‑protein gene (Fig.”
Purwati, P., Budiono, B., Rachman, B. E., Yulistiani, Y., Miatmoko, A., Nasronudin, N., Lardo, S., Purnama, Y. I., Laely, M., Rochmad, I., et al. (2021) · Biochemistry Research International · doi:10.1155/2021/6685921 · Cited by 16 · see citing works
“…murine protein model of SARS-CoV-1. protein has a high structural similarity to SARS-CoV-2 that N (nucleocapsid) protein directly influenced the secretion of IL-6 through NF-κβ [26]. previous discovery was strongly supported by the relation between IL-6 serological level and viral load counts [27].”
BackgroundThe Role of Glutathione in the Management of Cell-Mediated Immune Responses in Individuals with HIV
Lin, N., Erdos, T., Louie, C., Desai, R., Lin, N., Ayzenberg, G., & Venketaraman, V. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25052952 · Cited by 15 · see citing works
Structural proteins of human coronaviruses: what makes them different?
Minigulov, N., Boranbayev, K., Bekbossynova, A., Gadilgereyeva, B., & Filchakova, O. (2024) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2024.1458383 · Cited by 15 · see citing works
SARS-CoV-2 innate immune recognition and implications for respiratory health
Anang, V., Kumar, P., Pracha, J., Nho, R. S., Mora, A. L., Rojas, M. M., Gowdy, K. M., Yount, J. S., Bednash, J. S., Horowitz, J. C., et al. (2025) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2025.10.008 · Cited by 14 · see citing works
Fiorino, S., Tateo, F., de Biase, D., Gallo, C. G., Orlandi, P. E., Corazza, I., Budriesi, R., Micucci, M., Visani, M., Loggi, E., et al. (2021) · Future Microbiology · doi:10.2217/fmb-2021-0064 · Cited by 15 · see citing works
Dolci, M., Signorini, L., D’Alessandro, S., Perego, F., Parapini, S., Sommariva, M., Taramelli, D., Ferrante, P., Basilico, N., & Delbue, S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23074063 · Cited by 12 · see citing works
“It has been shown that SARS-CoV-2 proteins induce the expression and secretion of IL-6 preferentially by monocytes and macrophages, which are indeed the main cells involved in the production of cytokines [31,32].”
BackgroundLodi, G., Gentili, V., Casciano, F., Romani, A., Zauli, G., Secchiero, P., Zauli, E., Simioni, C., Beltrami, S., Fernández, M., et al. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1018761 · Cited by 12 · see citing works
“In particular, SARS-CoV-2 nucleocapsid protein (N) mediated IL-6 expression occurs via the direct binding of N protein on NF-κB promoter and via facilitation of the nuclear translocation of NF-κB (Zhang et al., 2007).”
BackgroundInfluentialInterferon β, an enhancer of the innate immune response against SARS-CoV-2 infection
Kali, S. K., Dröge, P., & Murugan, P. (2021) · Microbial Pathogenesis · doi:10.1016/j.micpath.2021.105105 · Cited by 12 · see citing works
“In SARS-CoV-1, N protein directly promotes IL-6 expression through NF-kB in vitro [23].”
Siu, K., Chan, C.-P., Chan, C., Zheng, B.-J., & Jin, D. (2009) · Journal of General Virology · doi:10.1099/vir.0.009209-0 · Cited by 11 · see citing works
Singh, S., Pandey, R., Tomar, S., Varshney, R., Sharma, D., & Gangenahalli, G. (2021) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-021-04217-y · Cited by 11 · see citing works
The Spanish flu as a worst case scenario?
Moxnes, J. F., & Christophersen, O. A. (2008) · Microbial Ecology in Health and Disease · doi:10.1080/08910600701699067 · Cited by 11 · see citing works
Hasan, A., Rahim, R., Nakayama, E. E., Uno, K., Hasan, N., Rahman, M., & Shioda, T. (2023) · Viruses · doi:10.3390/v15102018 · Cited by 10 · see citing works
“Zhang et al. showed the requirement for the 80 amino acid residues at the C terminus of the N protein of the SARS virus, a closely related coronavirus that emerged in 2003, for IL-6 production using the NF-kB transcription factor [40].”
Can data from paediatric cohorts solve the COVID-19 puzzle?
Do, L. A. H., Anderson, J., Mulholland, K., & Licciardi, P. V. (2020) · PLoS Pathogens · doi:10.1371/journal.ppat.1008798 · Cited by 10 · see citing works
- Authors
- Zhang, X., Wu, K., Wang, D., Yue, X., Song, D., Zhu, Y., & Wu, J.
- Affiliations
- Wuhan University (CN)
- Guangxi Normal University (CN)
- Corresponding author
- Wu, Kailang
- Zhu, Ying
- Wu, Jianguo
- Venue
- Virology
- Publisher
- Elsevier BV
- Published
- 2007-09
- Volume
- 365
- Issue
- 2
- Pages
- 324-335
- ISSN
- 0042-6822 (ISSN-L)
- PMC
- PMC7103332
- OpenAlex
- W2001975441
- Cited by
- 141
- References
- 43
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 4 · 2023: 12 · 2022: 19 · 2021: 26 · 2020: 43 · 2017: 3 · 2016: 1 · 2015: 2 · 2014: 1 · 2013: 4 · 2012: 1
- FWCI
- 2.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Virology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (30470087)
- Major State Basic Research Development Program of China (2005CB522901)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Keywords
- SARS-CoV, nucleocapsid protein, interleukin-6, NF-κB, transcriptional activation, promoter regulation, NF-κB nuclear translocation, viral pathogenesis, SARS
- MeSH terms
- Coronavirus Nucleocapsid Proteins, Cell Line, Cell Nucleus, Cytoplasm, Epithelial Cells, Humans, Luciferases, Lung, Mutation, Protein Binding, Interleukin-6, NF-kappa B, Sequence Deletion, Genes, Reporter, Nucleocapsid Proteins, Artificial Gene Fusion, Protein Transport, Electrophoretic Mobility Shift Assay, Severe acute respiratory syndrome-related coronavirus, Immunoprecipitation
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