Abstract
Protein arginine methylation, catalyzed by protein arginine methyltransferases (PRMTs), is implicated in modulation of cellular processes including gene transcription. The role of PRMTs in the regulation of intracellular signaling pathways has remained obscure, however. We now show that PRMT1 methylates apoptosis signal-regulating kinase 1 (ASK1) at arginine residues 78 and 80 and thereby negatively regulates ASK1 signaling. PRMT1-mediated ASK1 methylation attenuated the H2O2-induced stimulation of ASK1, with this inhibitory effect of PRMT1 being abolished by replacement of arginines 78 and 80 of ASK1 with lysine. Furthermore, depletion of PRMT1 expression by RNA interference potentiated H2O2-induced stimulation of ASK1. PRMT1-mediated ASK1 methylation promoted the interaction between ASK1 and its negative regulator thioredoxin, whereas it abrogated the association of ASK1 with its positive regulator TRAF2. Moreover, PRMT1 depletion potentiated paclitaxel-induced ASK1 activation and apoptosis in human breast cancer cells. Together, our results indicate that arginine methylation of ASK1 by PRMT1 contributes to the regulation of stress-induced signaling that controls a variety of cellular events including apoptosis.
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Abbreviations
- AdOx:
-
adenosine dialdehyde
- ASK1:
-
apoptosis signal-regulating kinase 1
- CCC:
-
COOH-terminal coiled-coil
- GFP:
-
green fluorescence protein
- HA:
-
hemagglutinin
- JNK:
-
c-Jun NH2-terminal kinase
- MAP:
-
mitogen-activated protein
- MTT:
-
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- NCC:
-
NH2-terminal coiled-coil
- PRMT:
-
protein arginine methyltransferase
- RNAi:
-
RNA interference
- ROS:
-
reactive oxygen species
- SAM:
-
S-adenosyl-L-methionine
- siRNA:
-
small interfering RNA
- TRAF:
-
TNF receptor-associated factor
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Acknowledgements
We thank Drs. H Ichijo for ASK1, RJ Davis for JNK1, H Hershmann for PRMT1, RM Evans for CARM1 and D Lim for PRMT5. This study was supported by a grant from the Korea Healthcare technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A090536) (E-JC).
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Cho, JH., Lee, MK., Yoon, K. et al. Arginine methylation-dependent regulation of ASK1 signaling by PRMT1. Cell Death Differ 19, 859–870 (2012). https://doi.org/10.1038/cdd.2011.168
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DOI: https://doi.org/10.1038/cdd.2011.168
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