Inhibition of the assembly of the RBPJ transcription complex is known to alleviate T cell exhaustion by suppressing PDL1 expression. However, the role of RBPJ in T cells, especially whether inhibition of the assembly of the RBPJ transcription complex is involved in the anti-tumor activity of T cells, remains largely unknown. In this study, we used co-immunoprecipitation to identify HUWE1 as the E3 ubiquitin ligase for RBPJ; combined application of CUT&Tag, ChIP/ATAC-qPCR, co-immunoprecipitation and flow cytometry indicated that RBPJ led to T cell dysfunction by reshaping the epigenetic landscape, enhancing the transcriptional activity or histone methylation/acetylation of exhausted genes; finally, virtual screening and molecular dynamics simulation were used to find that Acarbose reshaped the assembly of the RBPJ-RUVBL1/DNA ternary complex to disrupt the function of RBPJ. Our results not only revealed the mechanism by which RBPJ expression was induced in exhausted T cells, but also explained the molecular mechanism of how RBPJ exacerbated T cell exhaustion. Furthermore, the molecular conformational shaping of the RBPJ transcriptional complex by Acarbose provided new insights into the role of targeted inhibition of T cell exhaustion in the treatment of hepatocellular carcinoma.
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