GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE308nnn/GSE308448/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE308448GEOGSEfalseGene expression profiling of HBEpCs and Caco-2 cells during infection with WT SARS-CoV-2 or a recombinant SARS-CoV-2 deficient in PLpro deISGylation activityInterferon-stimulated gene 15 (ISG15) regulates diverse cellular processes, including antiviral immunity, through its conjugation to proteins, a process known as ISGylation. Several pathogens, including SARS-CoV-2, subvert ISGylation by encoding deISGylating enzymes. However, the direct targets and physiological consequences of coronaviral deISGylation remain poorly defined. Here, we engineered a recombinant SARS-CoV-2 harboring a mutant Nsp3 (Nsp3mut) with impaired papain-like protease (PLpro) deISGylating activity. Caco-2 and human bronchial epithelial (HBEpC) cells were infected with either wild-type or Nsp3mut SARS-CoV-2. Comparative transcriptomic profiling revealed that Nsp3mut infection led to a stronger induction of IFN- and ISG-related gene signatures compared to wild-type virus infection in both cell types. These results show that loss of PLpro-mediated deISGylation restores efficient antiviral innate immune responses during SARS-CoV-2 infection.2026/05/08GSE308448GSM9245722GSM9245733GSM9245723GSM9245734GSM9245735GSM9245724GSM9245725GSM9245736GSM9245740GSM9245730GSM9245741GSM9245742GSM9245731GSM9245732GSM9245726GSM9245737GSM9245727GSM9245738GSM9245739GSM9245728GSM924572934284308448Homo sapiens