A groundbreaking study conducted at the Global Health Institute, School of Life Sciences, EPFL, Lausanne, Switzerland, has uncovered a captivating aspect of SARS-CoV-2 infection. The study reveals that the virus manipulates a cell damage response pathway to optimize the activity of its fusion glycoprotein, Spike. This discovery adds complexity to our understanding of viral-host interactions and emphasizes the need for a holistic understanding of viral pathogenesis.
The research focused on the role of the host enzyme ZDHHC20 in the post-translational modification of Spike. The study found that SARS-CoV-2 infection induces a change in the transcriptional start site of the zdhhc20 gene, leading to the production of an extended version of the enzyme called ZDHHC20Long. This extended version exhibits significantly higher Spike acylating activity compared to the conventional counterpart.
Interestingly, the study also found that the transcriptional shift in zdhhc20 is not exclusive to SARS-CoV-2 infection. Other cellular challenges, such as chemically induced colitis and exposure to pore-forming toxins, trigger a similar transcriptional change. This suggests that SARS-CoV-2 exploits an existing cell damage response pathway to optimize its fusion glycoprotein.
The study compared Spike S-acylation during infection and transfection and found that SARS-CoV-2 infection leads to pronounced S-acylation compared to Spike transfection alone. This discrepancy prompted further investigation into the underlying molecular alterations. The researchers discovered that SARS-CoV-2 triggers a shift in the transcriptional start site of zdhhc20, resulting in the production of ZDHHC20Long. This extended enzyme is expressed not only in vitro but also in an in vivo infection model involving human ACE-2 transgenic mice.
The versatility of this transcriptional shift was also explored in response to chemically induced colitis and exposure to pore-forming toxins. ZDHHC20Long expression was detected in mouse colon tissue undergoing recovery after chemically induced colitis, suggesting a potential role in cellular repair processes. The findings indicate that ZDHHC20Long may be part of a universal response to danger or damage.
ZDHHC20Long exhibits distinctive characteristics compared to its conventional counterpart. It has a prolonged half-life and is exclusively localized to the Endoplasmic Reticulum (ER). This altered subcellular distribution raises questions about its functional implications and how it contributes to the enzyme’s enhanced activity.
The consequences of ZDHHC20Long’s expression on Spike modification were also investigated. Cells expressing ZDHHC20Long showed significantly faster and higher levels of Spike acylation compared to cells expressing the conventional ZDHHC20Short. ZDHHC20Long also reduced Spike deacylation, contributing to the stability of the fusion glycoprotein.
The study further explored the impact of ZDHHC20Long on SARS-CoV-2 infectivity. Viral particles produced in cells expressing ZDHHC20Long exhibited enhanced infectivity, as indicated by twofold higher viral RNA levels. These findings provide insights into the dynamics of viral replication and potential therapeutic interventions targeting ZDHHC20Long.
As the study unfolds the intricate interplay between SARS-CoV-2 and host cells, numerous questions arise for future research. Understanding the role of acylation in Spike incorporation into virions and the contribution of ZDHHC20Long to the host’s defense mechanisms during viral infection are among the exciting directions for further exploration.
In conclusion, this study expands our understanding of the molecular intricacies of SARS-CoV-2 infection and highlights the virus’s ability to exploit host cellular machinery for its benefit. It serves as a guiding beacon, leading us toward a more comprehensive comprehension of the intricate dance between viruses and their hosts. The study findings were published in the peer-reviewed journal Nature Communications.