Abstract
The ubiquitin E3 ligase UBE3A has been widely reported to interact with the proteasome, but it is still unclear how this enzyme regulates by ubiquitination the different proteasomal subunits. The proteasome receptor DDI1 has been identified both in Drosophila photoreceptor neurons and in human neuroblastoma cells in culture as a direct substrate of UBE3A. Here, we further characterize this regulation, by identifying the UBE3A-dependent ubiquitination sites and ubiquitin chains formed on DDI1. Additionally, we found one deubiquitinating enzyme that is capable of reversing the action of UBE3A on DDI1. The complete characterization of the ubiquitination pathway of an UBE3A substrate is important due to the role of this E3 ligase in rare neurological disorders as Angelman syndrome.
Highlights
The lack of functional UBE3A E3 ubiquitin ligase in the brain is responsible for a rare neurodevelopmental disorder called Angelman syndrome (AS)
From six ubiquitination sites detected on DDI1, we have discovered that the presence of K133 is necessary for DDI1 to be ubiquitinated by UBE3A
We recently discovered that Ube3a ubiquitinates endogenous Rngo in flies, and its human homolog DDI1 when transfected in S5-SYHY neuroblastoma cells (Ramirez et al, 2018)
Summary
The lack of functional UBE3A E3 ubiquitin ligase in the brain is responsible for a rare neurodevelopmental disorder called Angelman syndrome (AS). With an incidence of 1:15.000 births (Margolis et al, 2015), the disease is characterized by episodes of frequent laughter, language impairment, severe developmental delay, ataxic movements, hypopigmentation, seizure disorder, sleep disturbances, muscular hypotonia, and motor delay (Buiting et al, 2016). Clinical features of AS were first described in 1965, and since the diagnosis criteria has been well established (Williams et al, 2006). The role of UBE3A on the brain and how the lack of it can cause such a severe clinical scenario is still unknown
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