Arginine methylation of caspase-8 controls life/death decisions in extrinsic apoptotic networks

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 assa...

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Bibliographic Details
Published in:Oncogene 2024-06, Vol.43 (25), p.1955-1971
Main Authors: Wohlfromm, Fabian, Ivanisenko, Nikita V, Pietkiewicz, Sabine, König, Corinna, Seyrek, Kamil, Kähne, Thilo, Lavrik, Inna N
Format: Article
Language:English
Subjects:
Apoptosis
Caspase-8
Cell death
FasL protein
Mass spectroscopy
Methylation
Mutation
Post-translation
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Summary: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.
ISSN:0950-9232
1476-5594
1476-5594
DOI:10.1038/s41388-024-03049-6