期刊
CELL REPORTS
卷 21, 期 9, 页码 2447-2457出版社
CELL PRESS
DOI: 10.1016/j.celrep.2017.11.007
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资金
- Japan Society for the Promotion of Science (JSPS)
- Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT)
- KAKENHI on Innovative Areas Oxygen Biology: a new criterion for integrated understanding of life'' of MEXT [17H05518]
- KAKENHI on Innovative Areas New aspect of the ubiquitin system: its enormous roles in protein regulation'' of MEXT [15H01168]
- Mitsubishi Foundation
- Shimabara Science Promotion Foundation
- Japan Foundation of Applied Enzymology
- Life Science Foundation of Japan
- Fugaku Trust for Medicinal Research
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [15H01168, 17H05518, 15H04643, 16K15146, 16K15115] Funding Source: KAKEN
Apoptosis signal-regulating kinase 1 (ASK1) is an oxidative stress-responsive kinase that is regulated by various interacting molecules and post-translational modifications. However, how these molecules and modifications cooperatively regulate ASK1 activity remains largely unknown. Here, we showed that tripartite motif 48 (TRIM48) orchestrates the regulation of oxidative stress-induced ASK1 activation. A pull-down screen identified a TRIM48-interacting partner, protein arginine methyltransferase 1 (PRMT1), which negatively regulates ASK1 activation by enhancing its interaction with thioredoxin (Trx), another ASK1-negative regulator. TRIM48 facilitates ASK1 activation by promoting K48-linked polyubiquitination and degradation of PRMT1. TRIM48 knockdown suppressed oxidative stress-induced ASK1 activation and cell death, whereas forced expression promoted cancer cell death in mouse xenograft model. These results indicate that TRIM48 facilitates oxidative stress-induced ASK1 activation and cell death through ubiquitination-dependent degradation of PRMT1. This study provides a cell death mechanism fine-tuned by the crosstalk between enzymes that engage various types of post-translational modifications.
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