COVID-19 News: German And Japanese Study Finds That ORF3c Is Expressed In SARS-CoV-2-Infected Cells And Inhibits Innate Sensing By Targeting MAVS!

COVID-19 News: As the COVID-19 pandemic continues to shape our world, scientists worldwide are diligently working to unravel the mysteries of the SARS-CoV-2 virus. While the canonical proteins of this coronavirus have been extensively studied, there remain cryptic open reading frames (ORFs) within its genome that are less understood. One such enigmatic ORF is ORF3c, which is located within the viral genome and may hold the key to better understanding SARS-CoV-2's immune evasion strategies.


SARS-CoV-2-encoded ORF3c is expressed in infected cells. This small viral protein is conserved among
sarbecoviruses and suppresses the induction of IFN-β by targeting the signaling adaptor protein MAVS.
 -SARS-CoV-2 ORF3c is expressed in infected cells and suppresses IFN-β induction.
-SARS-CoV-2 ORF3c interacts with the signaling adaptor MAVS.
-SARS-CoV-2 ORF3c induces C-terminal cleavage of MAVS and inhibits its interaction with RIG-I.
-The immunosuppressive activity of ORF3c is conserved among sarbecoviruses.

SARS-CoV-2, like many other viruses, has evolved various mechanisms to evade the human immune system. This includes the suppression of type I interferon (IFN), a crucial element of the innate immune response. Since the onset of the pandemic, researchers have been diligently investigating these mechanisms, revealing a complex interplay of viral proteins. ORF3c is one of these viral proteins, and its role in immune evasion is the focus of this study.
 
In this COVID-19 News report, we will delve into the findings of a recent study conducted by scientists from University Hospital Tübingen-Germany, University Hospital, Friedrich-Alexander-Universität Erlangen-Nürnberg-Germany, The University of Tokyo-Japan, Charité – Universitätsmedizin Berlin-Germany, Humboldt-Universität zu Berlin, Germany, Berlin Institute of Health-Germany, and CREST, Japan Science and Technology Agency, Saitama-Japan. Their research centers on the expression of ORF3c in SARS-CoV-2-infected cells and its role in inhibiting innate immune sensing by targeting MAVS (mitochondrial antiviral-signaling protein).
 
ORF3c: A Mysterious Cryptic ORF
Within the genome of SARS-CoV-2, most proteins are encoded by subgenomic RNAs (sgRNAs). However, some viral mRNAs can encode more than one protein. One intriguing example is the ORF3a sgRNA, which encodes not only ORF3a but also ORF3c, a small 41-amino-acid peptide. ORF3c has remained an enigma in the realm of SARS-CoV-2 research, with its function and relevance to viral replication largely unknown.
 
While the existence of ORF3c has been known, its role in SARS-CoV-2 infection and immune evasion has been shrouded in mystery. This peptide's expression, exact function, and its contribution to efficient viral replication remained elusive questions. However, recent research has started to unravel the significance of ORF3c in the context of SARS-CoV-2 immune evasion.
 
Unmasking ORF3c 9;s Immune Evasion Abilities
In their study, the team of researchers identified ORF3c as a key player in the SARS-CoV-2 immune evasion arsenal. This small peptide, only 41 amino acids in length, was found to be expressed in virus-infected cells. Furthermore, ORF3c was found to actively suppress the induction of interferon-beta (IFN-β) expression, a critical component of the innate immune response.
 
Mechanistic analyses revealed that ORF3c exerts its immune evasion activity by inhibiting the sensing of viral infection by two important pattern recognition receptors (PRRs), RIG-I and MDA5. These receptors play a crucial role in detecting viral RNA and initiating an immune response. ORF3c interacts with the signaling adaptor MAVS, a key player in the antiviral signaling pathway. Notably, ORF3c induces the cleavage of the C-terminal domain of MAVS, thereby disrupting the MAVS-mediated signaling cascade. This cleavage prevents RIG-I from effectively interacting with MAVS, a crucial step in the initiation of the immune response.
 
The researchers observed that the immunosuppressive activity of ORF3c is not limited to SARS-CoV-2 but is also conserved among members of the sarbecovirus subgenus, which includes the original SARS-CoV virus and coronaviruses isolated from bats. This suggests that ORF3c's role in immune evasion is a common strategy employed by related viruses.
 
Variants and Compensatory Mechanisms
However, the story of ORF3c's role in SARS-CoV-2 is not entirely straightforward. While the peptide plays a role in immune evasion, the researchers noted that certain SARS-CoV-2 variants harbor premature stop codons in their ORF3c genes. This observation raises the question of whether ORF3c is essential for viral replication, and if so, how its loss is compensated.
 
Surprisingly, the disruption of ORF3c did not significantly impact SARS-CoV-2 replication in various cell lines, including CaCo-2, CaLu-3, and bat lung cells. This suggests that, at least in these in vitro settings, the virus can efficiently replicate without a functional ORF3c. Furthermore, these findings indicate that other viral proteins may compensate for the loss of ORF3c's immunosuppressive activity.
 
The researchers also noted that ORF3c is not the sole viral protein involved in immune evasion. SARS-CoV-2 employs multiple strategies to suppress the host's immune response. Proteins such as ORF10, ORF3b, nucleocapsid, ORF6, and ORF8 have all been identified as suppressors of IFN-β expression. The coexistence of multiple proteins with overlapping functions may act as a backup mechanism, ensuring the virus's survival even if one of these proteins is lost or inactivated.
 
The Evolutionary Mystery of ORF3c
The evolutionary trajectory of ORF3c adds another layer of intrigue to its story. It is clear that this small open reading frame has been subject to selective pressures, as different SARS-CoV-2 lineages have emerged with premature stop codons in their ORF3c genes. However, these variants, often referred to as SARS-CoV-2 lineages, continue to spread efficiently in the human population. This raises questions about the true significance of ORF3c in the context of viral replication.
 
The emergence of premature stop codons in ORF3c may not be a hindrance to the virus, but rather a part of its adaptive strategy. As the virus evolves, different selection pressures act on various regions of its genome. In the case of ORF3c, its loss may be compensated by other viral proteins or pathways. In essence, the virus has multiple tools at its disposal to achieve immune evasion, ensuring its continued replication and spread.
 
The enigmatic nature of ORF3c's role in SARS-CoV-2 evolution and immune evasion suggests that its significance may become more apparent in the context of in vivo infection. Experiments in animal models will be crucial to fully understand the impact of ORF3c on immune activation and viral replication in a living host.
 
Conclusion
In summary, the study discussed here sheds light on the role of ORF3c in the immune evasion strategies employed by SARS-CoV-2 and related sarbecoviruses. While it is clear that ORF3c can suppress the host's immune response by inhibiting IFN-β expression, its true importance in the overall viral replication process remains a subject of ongoing investigation.
 
The emergence of SARS-CoV-2 variants with truncated ORF3c genes demonstrates the adaptability and resilience of this virus. ORF3c may not be essential for efficient viral replication, but its presence or absence could influence other factors in the viral genome. The complex interplay of viral proteins involved in immune evasion highlights the intricate strategies employed by SARS-CoV-2 to ensure its survival and spread.
 
As the COVID-19 pandemic continues to evolve, our understanding of SARS-CoV-2 and its immune evasion mechanisms will undoubtedly grow. Future research, both in the laboratory and in the field, will provide further insights into the role of ORF3c and its contribution to the ongoing battle against this formidable virus.
 
The study findings were published in the peer reviewed journal: EMBO Reports.
https://www.embopress.org/doi/full/10.15252/embr.202357137
 
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