IBRDC2, an IBR-type E3 ubiquitin ligase, is a regulatory factor for Bax and apoptosis activation.
ABSTRACT Bax, a pro-apoptotic protein from the Bcl-2 family, is central to apoptosis regulation. To suppress spontaneous apoptosis, Bax must be under stringent control that may include regulation of Bax conformation and expression levels. We report that IBRDC2, an IBR-type RING-finger E3 ubiquitin ligase, regulates the levels of Bax and protects cells from unprompted Bax activation and cell death. Downregulation of IBRDC2 induces increased cellular levels and accumulation of the active form of Bax. The ubiquitination-dependent regulation of Bax stability is suppressed by IBRDC2 downregulation and stimulated by IBRDC2 overexpression in both healthy and apoptotic cells. Although mostly cytosolic in healthy cells, upon induction of apoptosis, IBRDC2 accumulates in mitochondrial domains enriched with Bax. Mitochondrial accumulation of IBRDC2 occurs in parallel with Bax activation and also depends on the expression levels of Bcl-xL. Furthermore, IBRDC2 physically interacts with activated Bax. By applying Bax mutants in HCT116 Bax(-/-) cells, combined with the use of active Bax-specific antibodies, we have established that both mitochondrial localization and apoptotic activation of Bax are required for IBRDC2 translocation to the mitochondria.
Article: Mitoplasticity: Adaptation biology of the mitochondrion to the cellular redox state in physiology and carcinogenesis.[show abstract] [hide abstract]
ABSTRACT: Significance: Adaptation and transformation biology of the mitochondrion to redox status is an emerging domain of physiology and pathophysiology. Mitochondrial adaptations occur in response to accidental changes in cellular energy demand or supply while mitochondrial transformations are part of greater program of cell metamorphosis. The possible role of mitochondrial adaptations and transformations in pathogenesis remains unexplored and it has become critical to decipher the stimuli and the underlying molecular pathways. Recent Advances: Immediate activation of mitochondrial function was described during acute exercise, respiratory chain injury, ER stress, genotoxic stress or environmental toxic insults. Delayed adaptations of mitochondrial form, composition and functions were evidenced for persistent changes in redox status as observed in endurance training, in fibroblasts grown in presence of respiratory chain inhibitors or in absence of glucose, in the smooth muscle of patients with severe asthma or in the skeletal muscle of patients with a mitochondrial disease. Besides, mitochondrial transformations were observed in the course of human cell differentiation, during immune response activation, or in cells undergoing carcinogenesis. Critical Issues: Little is known on the signals and downstream pathways which govern mitochondrial adaptations and transformations. Few adaptative loops including redox sensors, kinases and transcription factors were deciphered, but their implication in physiology and pathology remains elusive. Future Directions: Mitoplasticity could play a protective role against aging, diabetes, cancer or neurodegenerative diseases. Research on adaptation and transformation could allow the design of innovative therapies, notably in cancer.Antioxidants & Redox Signaling 09/2012; · 8.20 Impact Factor