ENDOU and infection: Using a recombinant wild-type SARS-CoV-2 (rWT) and a mutant with catalytically inactive EndoU (rH234A), we show that the EndoU activity is dispensable for viral replication in Vero cells but critically facilitates immune suppression and infection in physiologically relevant human lung cells, including human lung-derived epithelial cell lines, primary bronchial air-liquid interface cultures, and alveolar type 2 organoids derived from induced pluripotent stem cells.