Uncovering the biochemical mechanisms underlying different types of cell death has the potential to provide targets for the treatment of various diseases. A physiological cytokine combination (TNF+IFNγ) has been identified to induce cell death in several cell lines in vitro. However, because TNF and IFNγ are multi-effector cytokines, their individual and combined use has complex effects. In disease situations, it is difficult to distinguish which effects are triggered by TNF+IFNγ cell death.
A latest discovery by a research team led by Prof. AI Youwei from the Institute of Genetics and Developmental Biology (IGDB) of the Chinese Academy of Sciences provides new insights into answering this scientific question.
In this study, the researchers used RNA-seq and CRISPR-Cas9 genetic screening to show that IFNγ activates its transcription factor IRF1. It directly binds to specific interferon-sensitive response element (ISRE) positions in the CASP8 and CYLD promoters, upregulating their expression and promoting TNF-induced cell death through a synergistic effect.
In addition, they found that the IFNγ-upregulated CASP8 mRNA has a short half-life and requires stabilization by the RNA-binding protein ELAVL1 to translate sufficient protein to mediate cell death.
Therefore, in the future, simultaneous mutation of CASP8 and CYLD ISRE motifs in the promoter region in cancer cells or mouse genomes could be used to abolish the regulation of IFNγ on cell death and inhibit TNF+IFNγ-induced cell death. This opens the possibility to evaluate the role of TNF+IFNγ-induced cell death in immunotherapy and tissue damage.
This work, published in the Journal of Cell Biology, was supported by the National Key R&D Program of China, the National Natural Science Foundation of China, and the State Key Laboratory of Molecular Developmental Biology. Biochemical mechanism of TNF and IFNγ-induced cancer cell death. (Image by IGDB)
