Epigenetic landscape remodeled by the transcription factor RBPJ promotes tumor-infiltrating T cell exhaustion_HUWE1

The suppression of PDL1 expression through inhibition of the assembly of the RBPJ transcription complex has been shown to alleviate T cell exhaustion. However, the specific role of RBPJ in T cells, particularly its potential involvement in the anti-tumor activity of T cells, remains largely unexplored. In this research, immunoprecipitation was employed to identify HUWE1 as the E3 ubiquitin ligase for RBPJ. The integration of CUT&Tag, ChIP/ATAC-qPCR, immunoprecipitation, and flow cytometry analysis revealed that RBPJ induced T cell dysfunction through alterations in the epigenetic landscape, enhancement of transcriptional activity, and modulation of histone methylation/acetylation on exhaustion genes. Additionally, virtual screening and molecular dynamics simulation were utilized to demonstrate that Acarbose disrupted the function of RBPJ by reshaping the assembly of the RBPJ-RUVBL1/DNA ternary complex. Our findings elucidated the induction of RBPJ expression in exhausted T cells and the exacerbation of T cell exhaustion by RBPJ. Additionally, the molecular conformational changes of the RBPJ transcriptional complex induced by Acarbose shed light on the potential of targeted inhibition of T cell exhaustion for the treatment of hepatocellular carcinoma.