β-TrCP-dependent degradation of ASK1 suppresses the induction of the apoptotic response by oxidative stress
| Autor: | Ran Cheng, Hidenori Ichijo, Tohru Natsume, Shun-ichiro Iemura, Kazuki Hattori, Tomohisa Hatta, Isao Naguro, Kohsuke Takeda |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Ubiquitin-Protein Ligases Biophysics Apoptosis MAP Kinase Kinase Kinase 5 medicine.disease_cause Biochemistry 03 medical and health sciences Ubiquitin medicine Humans ASK1 Molecular Biology Caspase chemistry.chemical_classification Reactive oxygen species biology Chemistry Kinase Ubiquitination beta-Transducin Repeat-Containing Proteins Ubiquitin ligase Cell biology Oxidative Stress HEK293 Cells 030104 developmental biology Proteasome Proteolysis biology.protein Reactive Oxygen Species Oxidative stress |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - General Subjects. 1862:2271-2280 |
| ISSN: | 0304-4165 |
| Popis: | Apoptosis signal-regulating kinase 1 (ASK1) is a key player in the homeostatic response of many organisms. Of the many functions of ASK1, it is most well-known for its ability to induce canonical caspase 3-dependent apoptosis through the MAPK pathways in response to reactive oxygen species (ROS). As ASK1 is a regulator of apoptosis, its proper regulation is critical for the well-being of an organism. To date, several E3 ubiquitin ligases have been identified that are capable of degrading ASK1, signifying the importance of maintaining ASK1 expression levels during stress responses. ASK1 protein regulation under unstimulated conditions, however, is still largely unknown. Using tandem mass spectrometry, we have identified beta-transducin repeat containing protein (β-TrCP), an E3 ubiquitin ligase, as a novel interacting partner of ASK1 that is capable of ubiquitinating and subsequently degrading ASK1 through the ubiquitin-proteasome system (UPS). This interaction requires the seven WD domains of β-TrCP and the C-terminus of ASK1. By silencing the β-TrCP genes, we observed a significant increase in caspase 3 activity in response to oxidative stress, which could subsequently be suppressed by silencing ASK1. These findings suggest that β-TrCP is capable of suppressing oxidative stress-induced caspase 3-dependent apoptosis through suppression of ASK1, assisting in the organism's ability to maintain homeostasis in an unstable environment. |
| Databáze: | OpenAIRE |
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