Uncovering the biochemical mechanisms underlying different types of cell death holds the potential to provide targets for treating various diseases. Physiological cytokine combination (TNF+IFNγ) has been identified to induce cell death in various cell lines in vitro. However, due to TNF and IFNγ being multi-effector cytokines, their individual and combined use has complex effects. In disease situations, it is challenging to discern which effects are triggered by cell death induced by TNF+IFNγ.
The latest discovery by a research team led by Prof. Youwei Ai at the Institute of Genetics and Developmental Biology (IGDB) of the Chinese Academy of Sciences (CAS) provides new insights into answering this scientific question.
This study employed RNA-seq and CRISPR-Cas9 genetic screening, revealing that IFNγ activates its transcription factor IRF1. It directly binds to specific ISRE positions in the CASP8 and CYLD promoters, upregulating their expression and promoting TNF-induced cell death through a synergistic effect.
Additionally, the study found that the upregulated CASP8 mRNA by IFNγ has a short half-life and requires stabilization by the RNA-binding protein ELAVL1 to translate sufficient protein to mediate cell death.
Consequently, in the future, abolishing the regulation of IFNγ on cell death and inhibiting the cell death induced by TNF+IFNγ could be achieved through simultaneous mutation of CASP8 and CYLD ISRE motifs in the promoter region in cancer cells or mouse genomes. This opens the possibility to evaluate the role of cell death induced by TNF+IFNγ in immunotherapy and tissue damage.
Figure. Biochemical mechanism of TNF and IFNγ-induced cancer cell death. (Image by IGDB)
This work, published in the Journal of Cell Biology (doi: 10.1083/jcb.202305026), was supported by the National Key R&D Program of China (2022YFA1304500), the National Natural Science Foundation of China (32321004 and 22307139), the State Key Laboratory of Molecular Developmental Biology.
Contact:
Prof. AI Youwei
Institute of Genetics and Developmental Biology of the Chinese Academy of Sciences
Email: aiyouwei@genetics.ac.cn
CAS
中文
Figure. Biochemical mechanism of TNF and IFNγ-induced cancer cell death. (Image by IGDB)This work, published in the Journal of Cell Biology (doi: 10.1083/jcb.202305026), was supported by the National Key R&D Program of China (2022YFA1304500), the National Natural Science Foundation of China (32321004 and 22307139), the State Key Laboratory of Molecular Developmental Biology.Contact:Prof. AI YouweiInstitute of Genetics and Developmental Biology of the Chinese Academy of SciencesEmail: aiyouwei@genetics.ac.cn