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.


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.

MeSH terms

  • Apoptosis / genetics
  • Apoptosis / physiology
  • Cell Death / genetics
  • Cell Death / physiology*
  • Cell Line
  • Humans
  • MAP Kinase Kinase Kinase 5 / genetics
  • MAP Kinase Kinase Kinase 5 / metabolism*
  • Oxidative Stress / genetics
  • Oxidative Stress / physiology
  • Protein-Arginine N-Methyltransferases / genetics
  • Protein-Arginine N-Methyltransferases / metabolism*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Tripartite Motif Proteins / genetics
  • Tripartite Motif Proteins / metabolism*
  • Ubiquitin / metabolism
  • Ubiquitination / genetics
  • Ubiquitination / physiology


  • Repressor Proteins
  • Tripartite Motif Proteins
  • Ubiquitin
  • PRMT1 protein, human
  • Protein-Arginine N-Methyltransferases
  • MAP Kinase Kinase Kinase 5