Arginine methylation of caspase-8 controls life/death decisions in extrinsic apoptotic networks.
Fabian WohlfrommNikita V IvanisenkoSabine PietkiewiczCorinna KönigKamil SeyrekThilo KähneInna N LavrikPublished in: Oncogene (2024)
Procaspase-8 is a key mediator of death receptor (DR)-mediated pathways. Recently, the role of post-translational modifications (PTMs) of procaspase-8 in controlling cell death has received increasing attention. Here, using mass spectrometry screening, pharmacological inhibition and biochemical assays, we show that procaspase-8 can be targeted by the PRMT5/RIOK1/WD45 methylosome complex. Furthermore, two potential methylation sites of PRMT5 on procaspase-8, R233 and R435, were identified in silico. R233 and R435 are highly conserved in mammals and their point mutations are among the most common mutations of caspase-8 in cancer. The introduction of mutations at these positions resulted in inhibitory effects on CD95L-induced caspase-8 activity, effector caspase activation and apoptosis. In addition, we show that procaspase-8 can undergo symmetric di-methylation. Finally, the pharmacological inhibition of PRMT5 resulted in the inhibitory effects on caspase activity and apoptotic cell death. Taken together, we have unraveled the additional control checkpoint in procaspase-8 activation and the arginine methylation network in the extrinsic apoptosis pathway.
Keyphrases
- cell death
- cell cycle arrest
- genome wide
- dna methylation
- mass spectrometry
- nitric oxide
- dna damage
- oxidative stress
- working memory
- cancer therapy
- endoplasmic reticulum stress
- dendritic cells
- molecular docking
- high throughput
- risk assessment
- gene expression
- induced apoptosis
- amino acid
- squamous cell carcinoma
- climate change
- drug delivery
- immune response
- high performance liquid chromatography
- high resolution
- capillary electrophoresis
- type iii
- staphylococcus aureus
- lymph node metastasis
- squamous cell
- binding protein
- tandem mass spectrometry
- solid phase extraction