JNK mediates cell death by promoting the ubiquitination of the apurinic/apyrimidinic endonuclease APE1

• Main Authors: Tabanifar, Bahareh, Moorthy, Anbalagan, Tsai, Heng Hang, Kannan, Srinivasaraghavan, Verma, Chandra Shekhar, Sabapathy, Kanaga
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2023
• Subjects: Science::Biological sciences; Apoptosis; APE1
• Online Access: https://hdl.handle.net/10356/171372
• Institution: Nanyang Technological University

The c-Jun-NH2-terminal kinases (JNKs) regulate cell death, generally through the direct phosphorylation of both pro- and anti-apoptotic substrates. In this report, we demonstrate an alternate mechanism of JNK-mediated cell death involving the anti-apoptotic protein human apurinic/apyrimidinic endonuclease 1 (APE1). Treatment of cells with a variety of genotoxic stresses enhanced APE1-JNK (all isoforms of JNK1 or JNK2) interaction, specifically in cells undergoing apoptosis. Steady-state APE1 levels were decreased in these cells, in which APE1 is ubiquitinated and degraded in a JNK-dependent manner. Absence of JNKs reduced APE1 ubiquitination and increased its abundance. Mechanistically, the E3 ligase ITCH associates with both APE1 and JNK and is necessary for JNK-dependent APE1 ubiquitination and degradation. Structural models of the JNK-APE1 interaction support the observation of enhanced association of the complex in the presence of ubiquitin. The data together show a mechanism of JNK-mediated cell death by the degradation of APE1 through ITCH.