Roquin-2 promotes ubiquitin-mediated degradation of ASK1 to regulate stress responses

Takeshi Maruyama, Toshihiro Araki, Yosuke Kawarazaki, Isao Naguro, Susanne Heynen, Pedro Aza-Blanc, Ze'ev Ronai, Atsushi Matsuzawa, Hidenori Ichijo

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Apoptosis signal-regulating kinase 1 (ASK1, also known as MAP3K5) mediates reactive oxygen species (ROS)-induced cell death. When activated by ROS, ASK1 ultimately becomes ubiquitinated and degraded by the proteasome, a process that is antagonized by the biquitin-specific protease USP9X. Using a functional siRNA (small interfering RNA) screen in HeLa cells, we identified Roquin-2 (also called RC3H2) as an E3 ubiquitin ligase required for ROS-induced ubiquitination and degradation of ASK1. In cells treated with H2O2, knockdown of Roquin-2 promoted sustained activation of ASK1 and the downstream stress-responsive kinases JNK (c-Jun amino-terminal kinase) and p38 MAPK (mitogenactivated protein kinase), and led to cell death. The nematode Caenorhabditis elegans produces ROS as a defense mechanism in response to bacterial infection. In C. elegans, mutation of the gene encoding the Roquin-2 ortholog RLE-1 promoted accumulation of the activated form of the ASK1 ortholog NSY-1 and conferred resistance to infection by the bacteria Pseudomonas aeruginosa. Thus, these data suggest that degradation of ASK1 mediated by Roquin-2 is an evolutionarily conserved mechanism required for the appropriate regulation of stress responses, including pathogen resistance and cell death.

Original languageEnglish
JournalScience Signaling
Volume7
Issue number309
DOIs
Publication statusPublished - 2014 Jan 21
Externally publishedYes

Fingerprint

Ubiquitin
Reactive Oxygen Species
Cell death
Degradation
Cell Death
Caenorhabditis elegans
MAP Kinase Kinase Kinase 5
MAP Kinase Kinase 4
Gene encoding
Ubiquitin-Protein Ligases
JNK Mitogen-Activated Protein Kinases
Ubiquitination
p38 Mitogen-Activated Protein Kinases
Pathogens
Proteasome Endopeptidase Complex
HeLa Cells
Bacterial Infections
Pseudomonas aeruginosa
Small Interfering RNA
Bacteria

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Roquin-2 promotes ubiquitin-mediated degradation of ASK1 to regulate stress responses. / Maruyama, Takeshi; Araki, Toshihiro; Kawarazaki, Yosuke; Naguro, Isao; Heynen, Susanne; Aza-Blanc, Pedro; Ronai, Ze'ev; Matsuzawa, Atsushi; Ichijo, Hidenori.

In: Science Signaling, Vol. 7, No. 309, 21.01.2014.

Research output: Contribution to journalArticle

Maruyama, T, Araki, T, Kawarazaki, Y, Naguro, I, Heynen, S, Aza-Blanc, P, Ronai, Z, Matsuzawa, A & Ichijo, H 2014, 'Roquin-2 promotes ubiquitin-mediated degradation of ASK1 to regulate stress responses', Science Signaling, vol. 7, no. 309. https://doi.org/10.1126/scisignal.2004822
Maruyama, Takeshi ; Araki, Toshihiro ; Kawarazaki, Yosuke ; Naguro, Isao ; Heynen, Susanne ; Aza-Blanc, Pedro ; Ronai, Ze'ev ; Matsuzawa, Atsushi ; Ichijo, Hidenori. / Roquin-2 promotes ubiquitin-mediated degradation of ASK1 to regulate stress responses. In: Science Signaling. 2014 ; Vol. 7, No. 309.
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