RESUMEN
Abnormal protein accumulation is often observed in human neurodegenerative disorders such as polyglutamine diseases and Parkinson disease. Genetic and biochemical analyses indicate that valosin-containing protein (VCP) is a crucial molecule in the pathogenesis of human neurodegenerative disorders. We report here that VCP was specifically modified in neuronal cells with abnormal protein accumulation; this modification caused the translocation of VCP into the nucleus. Modification-mimic forms of VCP induced transcriptional suppression with deacetylation of core histones, leading to cell atrophy and the decrease of de novo protein synthesis. Preventing VCP nuclear translocation in polyglutamine-expressing neuronal cells and Drosophila eyes mitigated neurite retraction and eye degenerations, respectively, concomitant with the recovery of core histone acetylation. This represents a novel feedback mechanism that regulates abnormal protein levels in the cytoplasm during physiological processes, as well as in pathological conditions such as abnormal protein accumulation in neurodegenerations.
Asunto(s)
Adenosina Trifosfatasas/fisiología , Proteínas de Ciclo Celular/fisiología , Transcripción Genética , Transporte Activo de Núcleo Celular , Adenosina Trifosfatasas/química , Animales , Proteínas de Ciclo Celular/química , Línea Celular , Drosophila melanogaster/genética , Vectores Genéticos , Histonas/química , Humanos , Ratones , Ratones Transgénicos , Células 3T3 NIH , Enfermedades Neurodegenerativas/metabolismo , Neuronas/metabolismo , Células PC12 , Péptidos/genética , Péptidos/metabolismo , Ratas , Proteína que Contiene ValosinaRESUMEN
Catalase is a key antioxidant enzyme that catalyzes the decomposition of hydrogen peroxide (H2O2) to water and oxygen, and it appears to shuttle between the cytoplasm and peroxisome via unknown mechanisms. Valosin-containing protein (VCP) belongs to the AAA class of ATPases and is involved in diverse cellular functions, e.g. cell cycle and protein degradation, etc. Here we show that VCP and PEX19, a protein essential for peroxisome biogenesis, interact with each other. Knockdown of either VCP or PEX19 resulted in a predominantly cytoplasmic redistribution of catalase, and loss of VCP ATPase activity also increased its cytoplasmic redistribution. Moreover, VCP knockdown decreased intracellular ROS levels in normal and H2O2-treated cells, and an oxidation-resistant VCP impaired the ROS-induced cytoplasmic redistribution of catalase. These observations reveal a novel feedback mechanism, in which VCP can sense H2O2 levels, and regulates them by controlling the localization of catalase.