RRC ID 30483
Author Sekine Y, Hatanaka R, Watanabe T, Sono N, Iemura S, Natsume T, Kuranaga E, Miura M, Takeda K, Ichijo H.
Title The Kelch repeat protein KLHDC10 regulates oxidative stress-induced ASK1 activation by suppressing PP5.
Journal Mol. Cell
Abstract 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 H(2)O(2)-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.
Volume 48(5)
Pages 692-704
Published 2012-12-14
DOI 10.1016/j.molcel.2012.09.018
PII S1097-2765(12)00818-0
PMID 23102700
MeSH Animals Carrier Proteins / genetics Carrier Proteins / metabolism* Cell Death Cell Line, Tumor Cloning, Molecular Drosophila Proteins / genetics Drosophila Proteins / metabolism* Drosophila melanogaster / drug effects Drosophila melanogaster / genetics Drosophila melanogaster / metabolism* Enzyme Activation Gene Expression Regulation HEK293 Cells Humans Hydrogen Peroxide / pharmacology MAP Kinase Kinase Kinase 5 / genetics MAP Kinase Kinase Kinase 5 / metabolism* MAP Kinase Kinase Kinases / genetics MAP Kinase Kinase Kinases / metabolism* Melanins / metabolism Mice Mutagenesis, Site-Directed Nuclear Proteins / genetics Nuclear Proteins / metabolism* Oxidants / pharmacology Oxidative Stress* / drug effects Oxidative Stress* / genetics Phosphoprotein Phosphatases / genetics Phosphoprotein Phosphatases / metabolism* Point Mutation Protein Interaction Domains and Motifs Protein Interaction Mapping Proteomics RNA Interference Signal Transduction Time Factors Transfection Ubiquitin-Protein Ligases / metabolism p38 Mitogen-Activated Protein Kinases / metabolism
IF 14.248
Times Cited 19
Drosophila DGRC#109841 DGRC#109845 DGRC#109847