Researchers from the University of Liverpool and the University of Bristol have conducted a groundbreaking study that delves into the interaction between the NSP12 protein and host cell proteins in SARS-CoV-2. This study sheds light on the essential role of NSP12 in the virus’s biology and its intricate network of interactions with cellular proteins. While much attention has been focused on the spike protein mutation, this research highlights the significance of NSP12 in viral replication.
SARS-CoV-2, the virus responsible for the COVID-19 pandemic, has undergone significant genetic changes since its emergence in late 2019. Of particular interest are two mutations: the D614G substitution in the spike protein and the P323L substitution in the NSP12 protein. These mutations have led to the emergence of the globally dominant B.1 lineage. While the spike protein mutation has garnered more attention, the role of NSP12 P323L is equally critical in the viral replication complex.
The study aimed to investigate whether the NSP12 P323L substitution is a host adaptation mutation that alters its interaction with host cell proteins and affects viral RNA synthesis. Previous research has shown that host proteins interact with SARS-CoV-2 proteins, and amino acid substitutions in viral proteins can modify these interactions. The researchers employed biochemical and virological approaches to explore the interaction between NSP12 and host proteins.
The study’s findings confirmed that both variants of NSP12 interact with the TRiC protein complex, which plays a role in protein folding and stability. Additionally, the NSP12 variants exhibited different associations with components of a phosphatase complex. The researchers validated these interactions using various techniques and observed that some interactions were enhanced in the presence of NSP12 L323. Functional experiments demonstrated the importance of these interactions in SARS-CoV-2 replication, as the disruption of TRiC led to a significant decrease in viral RNA and protein levels.
This study provides valuable insights into the interplay between the NSP12 protein and host cell proteins in SARS-CoV-2. While the spike protein mutation has received significant attention, the NSP12 P323L substitution is not a mere bystander mutation but may confer a fitness advantage. The interactions between NSP12 and host proteins, particularly TRiC, are vital for viral replication. These findings emphasize the importance of considering viral protein-host protein interactions in virus adaptation. Understanding these molecular interactions is crucial for developing effective strategies against the ongoing pandemic and future viral threats. Further research in this area will contribute to our knowledge of SARS-CoV-2 biology and evolution.