Abstract
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. ASK1 is an oxidative stress-responsive kinase that regulates diverse cellular responses including cell death. Hirata et al. show that TRIM48 facilitates ubiquitination and degradation of the protein arginine methyltransferase PRMT1, an ASK1-negative regulator. This study uncovers a fine-tuning mechanism for ASK1 activation involving various types of post-translational modifications.
Original language | English |
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Pages (from-to) | 2447-2457 |
Number of pages | 11 |
Journal | Cell Reports |
Volume | 21 |
Issue number | 9 |
DOIs | |
Publication status | Published - 2017 Nov 28 |
Keywords
- ASK1
- MAPK
- PRMT1
- TRIM48
- apoptosis
- cancer
- oxidative stress
- tumor
- ubiquitin
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)