Study Uncovers SARS-CoV-2 Interaction with Fragile X Syndrome Proteins

A recent study, available on the preprint server bioRxiv, sheds light on how the SARS-CoV-2 virus, responsible for the COVID-19 pandemic, spreads through the body. Spearheaded by Professor Jakob Nilsson from the Novo Nordisk Center for Protein Research, the research team aimed to uncover which cellular machinery the virus targets during infection. 

Nilsson reveals that viruses typically hijack the body’s machinery to replicate or evade antiviral defenses. Surprisingly, the study uncovered that SARS-CoV-2 exploits proteins associated with fragile X syndrome, a genetic condition known for causing intellectual disability. Fragile X syndrome stems from mutations in the FMR1 gene and affects approximately 1 in 4,000 baby boys and 1 in 10,000 baby girls. 

The revelation of the virus’s interaction with fragile X-related proteins led the team, led by Postdoc Dimitriya Garvanska, to delve deeper into understanding this connection through various cell-biological and biochemical methods. They found that these proteins play a crucial role in the cell’s antiviral defense, which the virus aims to subvert for its propagation. 

This finding suggests a potential vulnerability for individuals with fragile X syndrome, implying they might be more susceptible to SARS-CoV-2 and other viral infections. Nilsson underscores the importance of heightened attention to these patients in the context of COVID-19. 

Moreover, the study provided insights into the mechanisms underlying fragile X syndrome. Fragile X-related proteins are essential for brain development, but the specifics of their importance were previously unclear. The research unveiled their interaction with UBAP2L, a protein influencing cellular protein production. Mutations in fragile X-related proteins disrupt this interaction, potentially shedding light on the syndrome’s pathophysiology. 

While primarily foundational, these findings hold promise for future therapeutic strategies. By unraveling the intricate mechanisms exploited by the virus, the researchers hope to pave the way for targeted interventions. 

To assess the significance of hijacking fragile X-related proteins, the team engineered a mutant virus targeting NSP3, a protein fragment crucial for binding to these proteins. Cell culture experiments demonstrated that the mutant virus’s ability to spread was diminished. Additionally, tests on hamsters revealed less severe lung impact during early infection stages with the mutated virus. 

Garvanska emphasizes the importance of these findings in elucidating the virus’s pathogenesis and potential avenues for therapeutic intervention. 

In summary, the study offers novel insights into the molecular interplay between SARS-CoV-2 and fragile X-related proteins, shedding light on both viral spread mechanisms and the pathophysiology of fragile X syndrome. These discoveries not only deepen our understanding of viral infections but also hold promise for future therapeutic developments. 

Journal Reference  

Dimitriya H. Garvanska et al, SARS-CoV-2 hijacks fragile X mental retardation proteins for efficient infection, bioRxiv (2023). DOI: 10.1101/2023.09.01.555899.