RESUMEN

The Uba6 (E1)-Use1 (E2) ubiquitin transfer cascade is a poorly understood alternative arm of the ubiquitin proteasome system (UPS) and is required for mouse embryonic development, independent of the canonical Uba1-E2-E3 pathway. Loss of neuronal Uba6 during embryonic development results in altered patterning of neurons in the hippocampus and the amygdala, decreased dendritic spine density, and numerous behavioral disorders. The levels of the E3 ubiquitin ligase Ube3a (E6-AP) and Shank3, both linked with dendritic spine function, are elevated in the amygdala of Uba6-deficient mice, while levels of the Ube3a substrate Arc are reduced. Uba6 and Use1 promote proteasomal turnover of Ube3a in mouse embryo fibroblasts (MEFs) and catalyze Ube3a ubiquitylation in vitro. These activities occur in parallel with an independent pathway involving Uba1-UbcH7, but in a spatially distinct manner in MEFs. These data reveal an unanticipated role for Uba6 in neuronal development, spine architecture, mouse behavior, and turnover of Ube3a.

Asunto(s)

Amígdala del Cerebelo/anomalías , Región CA3 Hipocampal/anomalías , Proteínas Qc-SNARE/deficiencia , Enzimas Activadoras de Ubiquitina/deficiencia , Ubiquitinación , Amígdala del Cerebelo/enzimología , Amígdala del Cerebelo/patología , Animales , Peso Corporal , Región CA3 Hipocampal/enzimología , Región CA3 Hipocampal/patología , Células Cultivadas , Espinas Dendríticas/patología , Desarrollo Embrionario , Metabolismo Energético , Femenino , Genes Letales , Discapacidades para el Aprendizaje/metabolismo , Locomoción , Masculino , Trastornos de la Memoria/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Microfilamentos , Proteínas del Tejido Nervioso/metabolismo , Consumo de Oxígeno , Estabilidad Proteica , Estructura Terciaria de Proteína , Proteínas Qc-SNARE/genética , Proteínas Qc-SNARE/fisiología , Proteínas SNARE , Conducta Social , Enzimas Activadoras de Ubiquitina/genética , Enzimas Activadoras de Ubiquitina/fisiología , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas de Transporte Vesicular