2. Academic Validation
  3. TRIM48 Promotes ASK1 Activation and Cell Death through Ubiquitination-Dependent Degradation of the ASK1-Negative Regulator PRMT1

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

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.

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