RESUMEN
Protein aggregates disrupt cellular homeostasis, causing toxicity linked to neurodegeneration. Selective autophagic elimination of aggregates is critical to protein quality control, but how aggregates are selectively targeted for degradation is unclear. We compared the requirements for autophagy receptor proteins: OPTN, NBR1, p62, NDP52, and TAX1BP1 in clearance of proteotoxic aggregates. Endogenous TAX1BP1 is recruited to and required for the clearance of stress-induced aggregates, whereas ectopic expression of TAX1BP1 increases clearance through autophagy, promoting viability of human induced pluripotent stem cell-derived neurons. In contrast, TAX1BP1 depletion sensitizes cells to several forms of aggregate-induced proteotoxicity. Furthermore, TAX1BP1 is more specifically expressed in the brain compared to other autophagy receptor proteins. In vivo, loss of TAX1BP1 results in accumulation of high molecular weight ubiquitin conjugates and premature lipofuscin accumulation in brains of young TAX1BP1 knockout mice. TAX1BP1 mediates clearance of a broad range of cytotoxic proteins indicating therapeutic potential in neurodegenerative diseases.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/deficiencia , Autofagia , Encéfalo/metabolismo , Péptidos y Proteínas de Señalización Intracelular/deficiencia , Proteínas de Neoplasias/deficiencia , Enfermedades Neurodegenerativas/metabolismo , Agregación Patológica de Proteínas/metabolismo , Animales , Proteínas Reguladoras de la Apoptosis/metabolismo , Encéfalo/patología , Femenino , Células HEK293 , Células HeLa , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Lipofuscina/genética , Lipofuscina/metabolismo , Masculino , Ratones , Ratones Noqueados , Proteínas de Neoplasias/metabolismo , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/patología , Agregación Patológica de Proteínas/genética , Agregación Patológica de Proteínas/patología , Ratas , Ratas Sprague-Dawley , Ubiquitina/genética , Ubiquitina/metabolismoRESUMEN
The VPS13 gene family consists of VPS13A-D in mammals. Although all four genes have been linked to human diseases, their cellular functions are poorly understood, particularly those of VPS13D. We generated and characterized knockouts of each VPS13 gene in HeLa cells. Among the individual knockouts, only VPS13D-KO cells exhibit abnormal mitochondrial morphology. Additionally, VPS13D loss leads to either partial or complete peroxisome loss in several transformed cell lines and in fibroblasts derived from a VPS13D mutation-carrying patient with recessive spinocerebellar ataxia. Our data show that VPS13D regulates peroxisome biogenesis.