Study Discovers The Impact of SARS-CoV-2 E and M Proteins On Host Cell Calcium Homeostasis And ER-Mitochondria Interactions
SARS-CoV-2 Research - E and M Proteins May 03, 2023 1 year, 2 months, 3 weeks, 3 days, 1 hour, 34 minutes ago
SARS-CoV-2 Research: COVID-19 is a highly infectious respiratory illness caused by the SARS-CoV-2 virus. It has led to millions of cases and deaths worldwide since the pandemic began in 2020. The virus has a single-stranded RNA genome enclosed in a capsid with four structural proteins, including the poorly understood envelope (E) protein. A new study by researchers from Columbia University-New York and University of Padova-Italy investigated the E and membrane (M) proteins of SARS-CoV-2 and their impact on host cell calcium (Ca2+) homeostasis and interorganelle contact sites.
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Coronaviruses such as SARS-CoV-2 are members of the Coronaviridae family, which are responsible for various respiratory illnesses. These viruses have four main proteins: spike (S), envelope (E), membrane (M), and nucleocapsid (N). The E and M proteins play crucial roles in virus assembly, invasion, replication, and release, but their specific actions on host cells are largely unexplored.
The E Protein
The E protein is the smallest and least understood of the four structural proteins. It is an integral membrane protein with one transmembrane domain, an intermediate helical domain, and hydrophilic N- and C-terminal domains. Studies have shown that the E protein can form ion channels in the viral membrane, which are essential for viral pathogenicity. The E protein's cation permeability is influenced by factors such as ion concentration, membrane composition, and pH. The E protein is also thought to play a significant role in respiratory inflammation via inflammasome activation.
The M Protein
The M protein interacts with itself, the S protein, and the N and E proteins to facilitate virus assembly and release. It is primarily located within the viral particle and plays a role in membrane bending, virus assembly, and replication.
Exploring the Role of E and M Proteins
This study examined the role of SARS-CoV-2 E and M proteins on host cell Ca2+ signaling. The researchers found that the proteins selectively affect endoplasmic reticulum (ER) and mitochondria Ca2+ handling in different ways. To overcome the low immunogenicity of the E protein, specific nanobodies were generated and tested against it. These nanobodies effectively targeted the E protein's function, suggesting that it could be a viable vaccine target and pointing to ER and mitochondrial Ca2+ handling as potential therapeutic targets.
Study Findings
The study found that the E and M proteins primarily localize in the ER, secretory compartments, and Golgi, affecting mitochondrial Ca2+ transients by selectively influencing the release of Ca2+ from the ER and contact sites between the ER and mitochondria. The M protein appears to play a more significant role in ER Ca2+ release, while the E protein selectively affects ER-mitochondria tethering.
The
SARS-CoV-2 Research team generated and isolated selective nanobodies to target the E protein's function. Electrophysiological recordings showed that these nanobodies could modulate the ion conductance of the E protein. When present in mammalian cells with the E protein, two nanobodies (clone A1 and E4) were sufficient to effic
iently revert the observed phenotype on mitochondrial Ca2+ uptake.
Conclusion
In summary, the research findings provide valuable insights into the roles of the SARS-CoV-2 E and M proteins in the host cell calcium homeostasis and ER-mitochondria contact sites. The E protein, in particular, stands out as a potential target for vaccine development and clinical management of COVID-19. The identified nanobodies offer a new avenue for designing drug regimens and immunotherapies to tackle SARS-CoV-2 infection and the associated disease.
Future research should focus on further understanding the molecular pathways through which the E and M proteins hijack the host cell machinery and the mechanisms that can be therapeutically targeted to halt the infection and disease progression. Additionally, studies should explore the potential of other structural proteins, such as the N protein, as targets for vaccines or drugs. Finally, the development of more effective nanobodies or other targeted therapies that can specifically disrupt the function of the E and M proteins may contribute significantly to the fight against COVID-19 and other coronaviruses.
The study findings were published in the peer reviewed journal: Cell Death and Disease.
https://www.nature.com/articles/s41419-023-05817-w
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