title: Ube3a, the E3 ubiquitin ligase causing Angelman syndrome and linked to autism, regulates protein homeostasis through the proteasomal shuttle Rpn10.
abstract: Ubiquitination, the covalent attachment of ubiquitin to a target protein, regulates most cellular processes and is involved in several neurological disorders. In particular, Angelman syndrome and one of the most common genomic forms of autism, dup15q, are caused respectively by lack of or excess of UBE3A, a ubiquitin E3 ligase. Its Drosophila orthologue, Ube3a, is also active during brain development. We have now devised a protocol to screen for substrates of this particular ubiquitin ligase. In a neuronal cell system, we find direct ubiquitination by Ube3a of three proteasome-related proteins Rpn10, Uch-L5, and CG8209, as well as of the ribosomal protein Rps10b. Only one of these, Rpn10, is targeted for degradation upon ubiquitination by Ube3a, indicating that degradation might not be the only effect of Ube3a on its substrates. Furthermore, we report the genetic interaction in vivo between Ube3a and the C-terminal part of Rpn10. Overexpression of these proteins leads to an enhanced accumulation of ubiquitinated proteins, further supporting the biochemical evidence of interaction obtained in neuronal cells.
authors.affiliation: CIC bioGUNE, Bizkaia Teknologia Parkea, Building 801-A, Derio, 48160, Derio, Basque Country, Spain.
authors.forename: So Young
authors.initials: SY
authors.lastname: Lee
authors.forename: Juanma
authors.initials: J
authors.lastname: Ramirez
authors.forename: Maribel
authors.initials: M
authors.lastname: Franco
authors.forename: Benoît
authors.initials: B
authors.lastname: Lectez
authors.forename: Monika
authors.initials: M
authors.lastname: Gonzalez
authors.forename: Rosa
authors.initials: R
authors.lastname: Barrio
authors.forename: Ugo
authors.initials: U
authors.lastname: Mayor
mesh_terms: D017204:Angelman Syndrome / Q000235:genetics; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D004330:Drosophila / Q000201:enzymology*; D029721:Drosophila Proteins / Q000378:metabolism / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D025941:Protein Interaction Mapping; D021381:Protein Transport; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism / Q000502:physiology*; D054875:Ubiquitination
chemical_list: D002352:Carrier Proteins; D029721:Drosophila Proteins; C498505:Rpn10 protein, Drosophila; C532444:Ube3a protein, Drosophila; D044767:Ubiquitin-Protein Ligases