Ubiquitin Proteasome System as a New Target to Fight Influenza A Virus

Medical News: Influenza A virus (IAV) has remained a serious global health concern, responsible for annual flu outbreaks and major health issues. With the virus constantly evolving, developing resistance to existing antiviral medications has become a growing challenge. Researchers are now exploring new therapeutic strategies. This Medical News report discusses a novel approach targeting the ubiquitin proteasome system (UPS) - the cell’s protein cleanup and recycling mechanism - to combat IAV infection. The study was conducted by researchers from The Ohio State University and funded by the U.S. National Institute of Allergy and Infectious Diseases and The Ohio State University Start-up Grant.


Ubiquitin Proteasome System as a New Target to Fight Influenza A Virus

What is the Ubiquitin Proteasome System?
The ubiquitin proteasome system (UPS) is a highly sophisticated cellular mechanism responsible for tagging and breaking down proteins within cells. It works like a cleanup crew, identifying unwanted proteins, tagging them with a molecule called ubiquitin, and sending them for recycling. This tagging and breakdown process is essential for cellular health. The system’s two main parts are the ubiquitin molecules (which tag the proteins) and the proteasome (which degrades them).
 
Viruses, including IAV, have found ways to manipulate the UPS, making it work in their favor. They hijack this cellular process to evade immune responses, replicate effectively, and spread within the host. The researchers in this study believe that understanding how IAV manipulates the UPS could reveal potential new treatment strategies.
 
How Influenza A Virus Exploits the Ubiquitin Proteasome System
IAV is known to exploit the UPS at several stages of its lifecycle. For example, it uses the system to increase the production of viral proteins, suppress host immune defenses, and release newly formed virus particles. By utilizing various UPS components, IAV can also regulate specific cellular proteins to control processes that facilitate viral replication. One of the key elements in this viral strategy involves E3 ligases and deubiquitinases.
 
-E3 Ligases: Helping the Virus Grow
E3 ligases are proteins within the UPS that help attach ubiquitin molecules to specific proteins, targeting them for breakdown or modifying their function. IAV has been observed to use E3 ligases to degrade host proteins that might otherwise stop viral infection. In particular, the viral polymerase PB2 is modified by host E3 ligases, which helps to enhance the virus’s polymerase activity without breaking down the protein, enabling effective replication. Additionally, the M1 protein is tagged by ubiquitin, facilitating the release of new virus particles from infected cells.
 
-Deubiquitinases (DUBs): Enabling Viral Replication
Deubiquitinases (DUBs) are enzymes that remove ubiquitin tags from proteins, stabilizing them and potentially influencing their function. By controlling DUB activity, IAV can regulat e the degradation of proteins that may otherwise interfere with viral replication. One example is USP11, which deubiquitinates and stabilizes viral nucleoproteins (NP), allowing the virus to continue replicating its RNA.
 
Host Defense: UPS Fights Back Against IAV
While IAV manipulates the UPS for its advantage, the system can also serve as a defense mechanism. Certain E3 ligases actively work to degrade viral proteins, disrupting IAV’s lifecycle. For instance, cyclophilin A, a protein within the UPS, tags viral M1 proteins for degradation. This process stops the virus from assembling and releasing new particles, thereby preventing further infection.
 
Some E3 ligases in the TRIM family, like TRIM14 and TRIM41, have shown potential in curbing IAV infection. TRIM14 binds to IAV’s nucleoproteins, marking them for degradation, while TRIM22 enhances the breakdown of viral components, ultimately restricting viral replication. These mechanisms represent the body’s efforts to counteract IAV infection through the UPS.
 
The Role of Deubiquitinases in Viral Entry and Immune Response
Research has revealed that DUBs also play roles beyond viral replication. Some DUBs aid viral entry by stabilizing viral entry proteins or components within the host cells. They can also impact immune responses, as certain DUBs influence the pathways that initiate immune defenses. In IAV infections, DUBs can limit the immune response, allowing the virus to escape detection and suppression.
 
For instance, the DUB known as OTUD3 regulates the production of an immune molecule called MAVS. MAVS triggers immune defenses, and when OTUD3 removes its ubiquitin tags, the immune system’s response weakens. Research suggests that during IAV infection, OTUD3’s function is suppressed to let the immune system mount a more robust response, showing that DUBs can act as double-edged swords in viral infection.
 
Potential Therapeutic Approaches Targeting the UPS
With the UPS playing a crucial role in the body’s response to IAV, researchers are exploring ways to target this system for therapeutic purposes. By modulating the UPS, they aim to strengthen the immune response against IAV while disrupting the virus’s ability to use the system to its advantage.
 
-Targeting E3 Ligases
By selectively inhibiting E3 ligases that assist IAV replication, new therapies may weaken the virus’s lifecycle. For instance, inhibiting the E3 ligase CNOT4, which helps IAV’s polymerase activity, could limit viral replication. Similarly, targeting E3 ligase FBXO45, which degrades immune response molecules, could enhance the immune system’s ability to combat the virus.
 
-Targeting Deubiquitinases
Inhibiting specific DUBs that IAV depends on for protein stabilization and immune evasion could also serve as a therapeutic approach. By disrupting the action of DUBs like USP11, which stabilizes viral nucleoproteins, researchers hope to hinder IAV’s replication abilities.
 
Small Molecules and PROTACs
Small molecules designed to interfere with specific components of the UPS have shown promise as potential therapies. PROTACs (proteolysis-targeting chimeras) are a novel class of compounds that can redirect UPS components to degrade particular proteins. Initial studies with PROTACs have shown promising results in targeting viral proteins, including those of the influenza virus.
 
Challenges and Future Directions
Targeting the UPS offers an innovative approach to combating IAV, yet it comes with challenges. Because the UPS is fundamental to numerous cellular processes, any therapy targeting this system must be highly selective to avoid unwanted side effects. Researchers are working on fine-tuning the design of drugs to ensure they specifically target viral or viral-assisted proteins without disrupting the entire UPS.

Further research will explore the intricacies of the UPS to uncover more specific targets within the system. Identifying E3 ligases and DUBs that play critical roles in viral infection may provide more focused avenues for intervention. Additionally, understanding the exact interplay between IAV and UPS components could pave the way for treatments not only for influenza but potentially other viral infections that exploit similar mechanisms.
 
Conclusion
This study highlights the complex relationship between IAV and the UPS, emphasizing the system’s dual role in aiding viral replication and offering potential defense mechanisms. By targeting the UPS components that facilitate IAV’s lifecycle, researchers hope to develop new therapeutic strategies. The interplay between viral manipulation and host defenses within the UPS holds promising avenues for flu treatment advancements. However, the delicate balance within this system necessitates careful consideration to ensure effective and safe therapeutic solutions.
 
The study findings were published in the peer-reviewed journal: Reviews in Medical Virology.
https://onlinelibrary.wiley.com/doi/10.1002/rmv.70005
 
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