Targeting sumoylation to inhibit SARS-CoV-2 replication cycle

Francesco Lotti, Assistant Professor of Pathology & Cell Biology, Department of Pathology and Cell Biology

Post-translational modifications are known to play important roles in the life cycles of certain viruses like human coronavirus. In particular, a process called sumoylation directly regulates viral replication, innate sensing pathways, and the innate immune response. Sumoylation occurs when small ubiquitin-like modifier (SUMO) proteins attach to and detach from other proteins to modulate their functions. Importantly, yeast two-hybrid screen identified Ubc9, the only E2 enzyme dedicated to sumoylation, as an interacting partner of SARS-CoV nuncleocapsid (N) protein (Fan et al., 2006). Biochemical analysis and mutagenesis studies demonstrated that the N protein was modified by sumoylation at lysine 62 (Li et al., 2005). Further characterization of wild type and K62A mutant N protein revealed that sumoylation promotes homo-oligomerization of the protein (Li et al., 2005). As self-association and homo-oligomerization of the N protein are essential for the formation of viral RNP and nucleocapsid assembly, sumoylation of this protein may play an important regulatory role in the SARS-CoV replication cycle.

Whether the N protein of the SARS-CoV-2, which causes COVID-19 is also sumoylated is not known. However, based on the close similarity between the N protein of the two coronaviruses, it is highly plausible that SARS-Cov-2 N protein is also modified by SUMO. Indeed, bioinformatic analysis of SARS-Cov-2 N protein predicts SUMO modification with high probability for several lysine residues, including lysine 62. The overall goal of this project is to investigate whether SARS-Cov-2 N protein is modified by SUMO and to delineate how sumoylation influences the replication cycle of SARS-CoV-2. Continued research in elucidating the dynamics of viral life cycle regulation by sumoylation is expected to yield novel therapeutic targets and to accelerate the design and development of antiviral therapies.