The Impact of SARS-CoV-2 E and M Proteins On Host Cell Calcium Homeostasis And ER-Mitochondria Interactions


The COVID-19 pandemic has caused significant damage globally, and despite the development of several vaccines, it continues to be a severe threat. The SARS-CoV-2 virus, responsible for the pandemic, is composed of four structural proteins, the S, N, E, and M proteins, which are critical for the assembly of the virus and its ability to infect cells.

While the S protein is the primary target of vaccine development, the E and M proteins have been relatively neglected, and their roles in the virus’ pathogenesis are not well understood.

In a recent study, the focus was on the E and M proteins and their ability to subvert cellular Ca2+ handling upon overexpression in mammalian HeLa cells. The E and M proteins are present on the viral envelope and are fundamental for the assembly of viruses through homotypic or heterotypic interactions.

The interactions between the E and M proteins occur in the ERGIC, while the homo-oligomerization of the E proteins leads to the formation of ion conductive pores in the viral membrane and viral assembly and budding at sites of intracellular transport, i.e., the ER, the Golgi complex, and ERGIC.

The study found that the M and E proteins are mainly localized in the ER, in secretory compartments, and the Golgi, impinging on mitochondria Ca2+ transients by selectively affecting the release of Ca2+ from the ER and the contact sites between the ER and mitochondria, respectively. The M protein appears to play a significant role in ER Ca2+ release, while the E protein selectively affects ER-mitochondria tethering. However, how they influence each other in modulating cellular Ca2+ signaling differently is still unclear.

Mitochondrial Ca2+ uptake was not significantly affected by the co-expression of the two proteins, indicating that additional mitochondria-related functions might be modulated. The small E protein, suggested to be involved in releasing Ca2+ out of the ER, was then targeted, and selective nanobodies were generated and isolated to target its function. Electrophysiological recordings demonstrated the ability of the selected nanobodies to modulate the ion conductance of the E protein.

Two nanobodies, clone A1 and E4, were found to be sufficient to efficiently revert the phenotype observed on mitochondrial Ca2+ uptake when present in mammalian cells along with the E protein. This suggests that the E protein might be an ideal target for vaccine and drug development, as well as a target for immunotherapies that not only trigger a directed immune response but also directly interfere with the regulation and function of the target protein to fight SARS-CoV-2 infection and COVID-19 disease.

The study’s findings suggest that the E and M proteins play important roles in SARS-CoV-2 pathogenesis by influencing cellular Ca2+ signaling. The selective targeting of the E protein through nanobodies provides a potential avenue for the development of therapeutics to combat COVID-19. Additionally, understanding the roles of the E and M proteins in viral assembly and their interactions with each other could contribute to the development of new strategies to prevent viral replication and infection.

The study highlights the importance of considering all the structural proteins of the SARS-CoV-2 virus when developing vaccines and therapeutics. While the S protein is currently the primary target of vaccine development, the E and M proteins should not be overlooked. Further research is needed to better understand their roles in viral pathogenesis and to identify additional targets for vaccine and drug development.

Moreover, the role of these “neglected” structural proteins, E and M, in SARS-CoV-2 infection and pathogenesis remains to be fully understood. However, recent studies have shed some light on their potential involvement in the viral life cycle and host response to infection.

One study demonstrated that the E protein of SARS-CoV-2 can activate the NLRP3 inflammasome, a key component of the innate immune response, leading to the production of pro-inflammatory cytokines and contributing to the pathogenesis of COVID-19 [60]. Another study suggested that the M protein of SARS-CoV-2 can interact with the host protein TMEM41B to promote viral replication and virion release [61]. These findings highlight the potential importance of the E and M proteins in the host-virus interaction and pathogenesis of COVID-19.

Furthermore, the ability of the E and M proteins to modulate cellular Ca2+ handling suggests that they may also play a role in other cellular processes beyond viral assembly and pathogenesis. Calcium ions are critical signaling molecules that regulate a wide range of cellular functions, including muscle contraction, neuronal signaling, gene expression, and cell proliferation and death. Disruption of calcium homeostasis can lead to various pathological conditions, including neurodegenerative diseases, cardiovascular diseases, and cancer.

Thus, targeting the E and M proteins of SARS-CoV-2 could have broad therapeutic potential beyond the treatment of COVID-19. For instance, modulating the ion conductance of the E protein using selective nanobodies, as demonstrated in the present study, could potentially be used to treat other conditions associated with calcium dysregulation, such as cardiac arrhythmias and neurodegenerative diseases.

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