TRIM48 Promotes ASK1 Activation and Cell Death through Ubiquitination-Dependent Degradation of the ASK1-Negative Regulator PRMT1

Yusuke Hirata, Kazumi Katagiri, Keita Nagaoka, Tohru Morishita, Yuki Kudoh, Tomohisa Hatta, Isao Naguro, Kuniyuki Kano, Tsuyoshi Udagawa, Tohru Natsume, Junken Aoki, Toshifumi Inada, Takuya Noguchi, Hidenori Ichijo, Atsushi Matsuzawa

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

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 languageEnglish
Pages (from-to)2447-2457
Number of pages11
JournalCell Reports
Volume21
Issue number9
DOIs
Publication statusPublished - 2017 Nov 28

Keywords

  • ASK1
  • MAPK
  • PRMT1
  • TRIM48
  • apoptosis
  • cancer
  • oxidative stress
  • tumor
  • ubiquitin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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