Activation of the Ca<sup>2+</sup>/NFAT Pathway by Assembly of Hepatitis C Virus Core Protein into Nucleocapsid-like Particles
Hepatitis C virus (HCV) is the primary pathogen responsible for liver cirrhosis and hepatocellular carcinoma. The main virion component, the core (C) protein, has been linked to several aspects of HCV pathology, including oncogenesis, immune evasion and stress responses. We and others have previousl...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-04-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/14/4/761 |
| _version_ | 1797408985788186624 |
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| author | Priya Devi Tanel Punga Anders Bergqvist |
| author_facet | Priya Devi Tanel Punga Anders Bergqvist |
| author_sort | Priya Devi |
| collection | DOAJ |
| description | Hepatitis C virus (HCV) is the primary pathogen responsible for liver cirrhosis and hepatocellular carcinoma. The main virion component, the core (C) protein, has been linked to several aspects of HCV pathology, including oncogenesis, immune evasion and stress responses. We and others have previously shown that C expression in various cell lines activates Ca<sup>2+</sup> signaling and alters Ca<sup>2+</sup> homeostasis. In this study, we identified two distinct C protein regions that are required for the activation of Ca<sup>2+</sup>/NFAT signaling. In the basic N-terminal domain, which has been implicated in self-association of C, amino acids 1–68 were critical for NFAT activation. Sedimentation analysis of four mutants in this domain revealed that association of the C protein into nucleocapsid-like particles correlated with NFAT-activated transcription. The internal, lipid droplet-targeting domain was not required for NFAT-activated transcription. Finally, the C-terminal ER-targeting domain was required in extenso for the C protein to function. Our results indicate that targeting of HCV C to the ER is necessary but not sufficient for inducing Ca<sup>2+</sup>/NFAT signaling. Taken together, our data are consistent with a model whereby proteolytic intermediates of C with an intact transmembrane ER-anchor assemble into pore-like structures in the ER membrane. |
| first_indexed | 2024-03-09T04:07:46Z |
| format | Article |
| id | doaj.art-741db5af0a914525bf67927f2ad5b4e6 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-09T04:07:46Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-741db5af0a914525bf67927f2ad5b4e62023-12-03T14:04:13ZengMDPI AGViruses1999-49152022-04-0114476110.3390/v14040761Activation of the Ca<sup>2+</sup>/NFAT Pathway by Assembly of Hepatitis C Virus Core Protein into Nucleocapsid-like ParticlesPriya Devi0Tanel Punga1Anders Bergqvist2Department of Medical Sciences, Uppsala University, SE 75185 Uppsala, SwedenDepartment of Medical Biochemistry and Microbiology, Uppsala University, SE 75123 Uppsala, SwedenDepartment of Medical Sciences, Uppsala University, SE 75185 Uppsala, SwedenHepatitis C virus (HCV) is the primary pathogen responsible for liver cirrhosis and hepatocellular carcinoma. The main virion component, the core (C) protein, has been linked to several aspects of HCV pathology, including oncogenesis, immune evasion and stress responses. We and others have previously shown that C expression in various cell lines activates Ca<sup>2+</sup> signaling and alters Ca<sup>2+</sup> homeostasis. In this study, we identified two distinct C protein regions that are required for the activation of Ca<sup>2+</sup>/NFAT signaling. In the basic N-terminal domain, which has been implicated in self-association of C, amino acids 1–68 were critical for NFAT activation. Sedimentation analysis of four mutants in this domain revealed that association of the C protein into nucleocapsid-like particles correlated with NFAT-activated transcription. The internal, lipid droplet-targeting domain was not required for NFAT-activated transcription. Finally, the C-terminal ER-targeting domain was required in extenso for the C protein to function. Our results indicate that targeting of HCV C to the ER is necessary but not sufficient for inducing Ca<sup>2+</sup>/NFAT signaling. Taken together, our data are consistent with a model whereby proteolytic intermediates of C with an intact transmembrane ER-anchor assemble into pore-like structures in the ER membrane.https://www.mdpi.com/1999-4915/14/4/761HCVcore proteinSPP cleavageERcalciumNFAT |
| spellingShingle | Priya Devi Tanel Punga Anders Bergqvist Activation of the Ca<sup>2+</sup>/NFAT Pathway by Assembly of Hepatitis C Virus Core Protein into Nucleocapsid-like Particles Viruses HCV core protein SPP cleavage ER calcium NFAT |
| title | Activation of the Ca<sup>2+</sup>/NFAT Pathway by Assembly of Hepatitis C Virus Core Protein into Nucleocapsid-like Particles |
| title_full | Activation of the Ca<sup>2+</sup>/NFAT Pathway by Assembly of Hepatitis C Virus Core Protein into Nucleocapsid-like Particles |
| title_fullStr | Activation of the Ca<sup>2+</sup>/NFAT Pathway by Assembly of Hepatitis C Virus Core Protein into Nucleocapsid-like Particles |
| title_full_unstemmed | Activation of the Ca<sup>2+</sup>/NFAT Pathway by Assembly of Hepatitis C Virus Core Protein into Nucleocapsid-like Particles |
| title_short | Activation of the Ca<sup>2+</sup>/NFAT Pathway by Assembly of Hepatitis C Virus Core Protein into Nucleocapsid-like Particles |
| title_sort | activation of the ca sup 2 sup nfat pathway by assembly of hepatitis c virus core protein into nucleocapsid like particles |
| topic | HCV core protein SPP cleavage ER calcium NFAT |
| url | https://www.mdpi.com/1999-4915/14/4/761 |
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