β-TrCP-dependent degradation of ASK1 suppresses the induction of the apoptotic response by oxidative stress.
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.
['Cheng|Ran|R|', 'Takeda|Kohsuke|K|', 'Naguro|Isao|I|', 'Hatta|Tomohisa|T|', 'Iemura|Shun-Ichiro|SI|', 'Natsume|Tohru|T|', 'Ichijo|Hidenori|H|', 'Hattori|Kazuki|K|']
D017209:Apoptosis D057809:HEK293 Cells D006801:Humans D048848:MAP Kinase Kinase Kinase 5 D018384:Oxidative Stress D059748:Proteolysis D017382:Reactive Oxygen Species D025801:Ubiquitin D044767:Ubiquitin-Protein Ligases D054875:Ubiquitination D044844:beta-Transducin Repeat-Containing Proteins
ASK1 Oxidative stress Apoptosis E3 ubiquitin ligase β-TrCP Ubiquitin-proteasome system