CHIP E3 Ligase and USP2 Deubiquitinating Enzyme Antagonistically Control AIF‐mediated Programmed Cell Death

• DOI: 10.1096/fasebj.24.1_supplement.842.3
• Publication Date: 2021-06-15T18:26:18Z
• Authors: Seung Wook Yang; Kyu Hee Oh; Jung Mi Park; Young Joo Jeon; Chin Ha Chung
• Keywords: 0301 basic medicine; 03 medical and health sciences

Under normal conditions, apoptosis inducing factor (AIF) in the mitochondrial membrane functions as an oxidoreductase that scavenges reactive oxygen species. Under certain stresses, such as exposure to N‐methyl‐N′‐nitro‐N′‐nitrosoguanidine (MNNG), AIF is truncated from the mitochondria and translocated to the nucleus, where it induces caspase‐independent programmed cell death, featured by chromatin condensation and large‐scale DNA breakage. Here we demonstrate that USP2 deubiquitinates AIF whereas CHIP functions as an ubiquitin E3 ligase of AIF, thus controlling the stability of AIF. Expression of USP2 resulted in acceleration of AIF‐mediated apoptotic process in HeLa cells, whereas that of CHIP attenuates it. Consistently, CHIP−/− mouse embryonic fibroblast (MEF) cells showed an increased sensitivity to MNNG. Collectively, these results indicate that CHIP and USP2 display antagonistic roles in the regulation of AIF‐mediated, caspase‐independent apoptosis.