TY - JOUR
T1 - The Kelch Repeat Protein KLHDC10 Regulates Oxidative Stress-Induced ASK1 Activation by Suppressing PP5
AU - Sekine, Yusuke
AU - Hatanaka, Ryo
AU - Watanabe, Takeshi
AU - Sono, Naoki
AU - Iemura, Shun ichiro
AU - Natsume, Tohru
AU - Kuranaga, Erina
AU - Miura, Masayuki
AU - Takeda, Kohsuke
AU - Ichijo, Hidenori
N1 - Funding Information:
We thank T. Adachi-Yamada, T. Aigaki, and S.B. Carroll for fly strains; Y. Hiromi and R. Ueda for plasmids; and the Bloomington Drosophila Stock Center, the Drosophila Genetic Resource Center at Kyoto Institute of Technology, NIG-FLY stock center, and the Vienna Drosophila RNAi Center for fly strains. We are grateful to all the members of the Laboratory of Cell Signaling for their critical comments. This work was supported by KAKENHI from JSPS and MEXT, Strategic Approach to Drug Discovery and Development in Pharmaceutical Sciences, GCOE Program, the “Understanding of molecular and environmental bases for brain health” conducted under the Strategic Research Program for Brain Sciences by MEXT, the Advanced Research for Medical Products Mining Programme of the National Institute of Biomedical Innovation, the Naito Foundation Natural Science Scholarship, the Cosmetology Research Foundation, and the Tokyo Biochemical Research Foundation.
PY - 2012/12/14
Y1 - 2012/12/14
N2 - Reactive oxygen species (ROS)-induced activation of Apoptosis signal-regulating kinase 1 (ASK1) plays crucial roles in oxidative stress-mediated cell death through the activation of the JNK and p38 MAPK pathways. However, the regulatory mechanism of ASK1 in the oxidative stress response remains to be elucidated. Here, we identified the kelch repeat protein, Slim, as an activator of ASK1 through a Drosophila misexpression screen. We also performed a proteomics screen and revealed that Kelch domain containing 10 (KLHDC10), a mammalian ortholog of Slim, interacted with Protein phosphatase 5 (PP5), which has been shown to inactivate ASK1 in response to ROS. KLHDC10 bound to the phosphatase domain of PP5 and suppressed its phosphatase activity. Moreover, KLHDC10 was required for H2O2-induced sustained activation of ASK1 and cell death in Neuro2A cells. These findings suggest that Slim/KLHDC10 is an activator of ASK1, contributing to oxidative stress-induced cell death through the suppression of PP5.
AB - Reactive oxygen species (ROS)-induced activation of Apoptosis signal-regulating kinase 1 (ASK1) plays crucial roles in oxidative stress-mediated cell death through the activation of the JNK and p38 MAPK pathways. However, the regulatory mechanism of ASK1 in the oxidative stress response remains to be elucidated. Here, we identified the kelch repeat protein, Slim, as an activator of ASK1 through a Drosophila misexpression screen. We also performed a proteomics screen and revealed that Kelch domain containing 10 (KLHDC10), a mammalian ortholog of Slim, interacted with Protein phosphatase 5 (PP5), which has been shown to inactivate ASK1 in response to ROS. KLHDC10 bound to the phosphatase domain of PP5 and suppressed its phosphatase activity. Moreover, KLHDC10 was required for H2O2-induced sustained activation of ASK1 and cell death in Neuro2A cells. These findings suggest that Slim/KLHDC10 is an activator of ASK1, contributing to oxidative stress-induced cell death through the suppression of PP5.
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U2 - 10.1016/j.molcel.2012.09.018
DO - 10.1016/j.molcel.2012.09.018
M3 - Article
C2 - 23102700
AN - SCOPUS:84870878552
VL - 48
SP - 692
EP - 704
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 5
ER -