Although previous studies have shown that host SUMOylation plays a role in SARS-CoV-2 infection, including the SUMOylation of the ACE2 receptor and N protein 12, 14, our study identified for the first time the SUMOylation of the viral structural protein Spike and its heterogeneous regulation via different SUMO isoforms for viral infection. This evidence concerns the gene CHMP5 and viral infectious disease.