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

  • Cell Rep. 2017 Nov 28;21(9):2447-2457. doi: 10.1016/j.celrep.2017.11.007.
Yusuke Hirata  1 ,  Kazumi Katagiri  2 ,  Keita Nagaoka  1 ,  Tohru Morishita  1 ,  Yuki Kudoh  1 ,  Tomohisa Hatta  3 ,  Isao Naguro  2 ,  Kuniyuki Kano  4 ,  Tsuyoshi Udagawa  5 ,  Tohru Natsume  3 ,  Junken Aoki  4 ,  Toshifumi Inada  5 ,  Takuya Noguchi  1 ,  Hidenori Ichijo  2 ,  Atsushi Matsuzawa  6
Affiliations
  • 1. Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
  • 2. Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
  • 3. Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
  • 4. Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
  • 5. Laboratory of Gene Regulation, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
  • 6. Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. Electronic address: [email protected].
PMID: 29186683 DOI: 10.1016/j.celrep.2017.11.007
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.

Keywords
ASK1; MAPK; PRMT1; TRIM48; apoptosis; cancer; oxidative stress; tumor; ubiquitin.