Angelman syndrome is a complex neurodevelopmental disorder caused by the lack of function in the brain of a single gene, UBE3A. The E3 ligase coded by this gene is known to build K48-linked ubiquitin chains, a modification historically considered to target substrates for degradation by the proteasome. However, a change in protein abundance is not proof that a candidate UBE3A substrate is indeed ubiquitinated by UBE3A. We have here used an unbiased ubiquitin proteomics approach, the bioUb strategy, to identify 79 proteins that appear more ubiquitinated in the Drosophila photoreceptor cells when Ube3a is over-expressed. We found a significantly high number of those proteins to be proteasomal subunits or proteasome-interacting proteins, suggesting a wide proteasomal perturbation in the brain of Angelman patients. We focused on validating the ubiquitination by Ube3a of Rngo, a proteasomal component conserved from yeast (Ddi1) to humans (DDI1 and DDI2), but yet scarcely characterized. Ube3a-mediated Rngo ubiquitination in fly neurons was confirmed by immunoblotting. Using human neuroblastoma SH-SY5Y cells in culture, we also observed that human DDI1 is ubiquitinated by UBE3A, without being targeted for degradation. The novel observation that DDI1 is expressed in the developing mice brain, with a significant peak at E16.5, strongly suggests that DDI1 has biological functions not yet described that could be of relevance for Angelman syndrome clinical research.

• MeSH
• Angelmanův syndrom genetika   patofyziologie   MeSH
• aspartátové proteasy genetika   MeSH
• Drosophila MeSH
• fotoreceptory metabolismus   patologie   MeSH
• lidé MeSH
• myši MeSH
• neurony metabolismus   patologie   MeSH
• proteiny Drosophily genetika   MeSH
• proteomika MeSH
• regulace genové exprese genetika   MeSH
• Saccharomyces cerevisiae - proteiny genetika   MeSH
• ubikvitinace genetika   MeSH
• ubikvitinligasy genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aspartátové proteasy MeSH
• DDI1 protein, S cerevisiae MeSH Prohlížeč
• DDI2 protein, human MeSH Prohlížeč
• proteiny Drosophily MeSH
• Saccharomyces cerevisiae - proteiny MeSH
• Ube3a protein, Drosophila MeSH Prohlížeč
• UBE3A protein, human MeSH Prohlížeč
• ubikvitinligasy MeSH