Homo sapiens Raw sequence reads

GBP5, an interferon-stimulated gene, plays a crucial role in cell autonomous immunity against intracellular pathogens. Our previous studies have linked GBP5 to inflammatory bowel diseases, suggesting its involvement in driving inflammatory activities. Here, we aim to elucidate the underlying mechanism behind the pro-inflammatory role of GBP5. In mononuclear cell line THP-1, we observed that GBP5 deficiency led to reduced expression of numerous pro-inflammatory genes, and their restoration upon GBP5 re-introduction. In a GBP5 knockout mouse model fed with dextran sulfite sodium (DSS), we demonstrated that GBP5 deficiency mitigated colonic inflammation. For mechanistic insights, transcriptome analysis revealed that, altered gene expression in the GBP5 deficient THP-1 cells mirrored those of STAT1 activation. CHIP-seq analysis demonstrated that GBP5 is not a transcription factor. On the other hand, GBP5 stimulated STAT1 expression and facilitated its translocation from the cytoplasm to the nucleus. Further, co-immunoprecipitation followed by mass spectrometry identified STAT1 as a GBP5 binding protein, which was confirmed by Western blots. In conclusion, our findings establish GBP5 as a key trigger molecule for intestinal inflammation in inflammatory bowel diseases, with the pro-inflammatory effect mediated through STAT1. Furthermore, GBP5 may enhance STAT1 expression and promote its nuclear translocation.