Research Article

Cellular and Molecular Life Sciences

, Volume 71, Issue 14, pp 2747-2758

First online:

Ube3a, the E3 ubiquitin ligase causing Angelman syndrome and linked to autism, regulates protein homeostasis through the proteasomal shuttle Rpn10

  • So Young LeeAffiliated withCIC bioGUNE, Bizkaia Teknologia Parkea
  • , Juanma RamirezAffiliated withCIC bioGUNE, Bizkaia Teknologia Parkea
  • , Maribel FrancoAffiliated withCIC bioGUNE, Bizkaia Teknologia ParkeaInstituto de Neurociencias CSIC/UMH
  • , Benoît LectezAffiliated withCIC bioGUNE, Bizkaia Teknologia Parkea
  • , Monika GonzalezAffiliated withCIC bioGUNE, Bizkaia Teknologia Parkea
  • , Rosa BarrioAffiliated withCIC bioGUNE, Bizkaia Teknologia Parkea
  • , Ugo MayorAffiliated withCIC bioGUNE, Bizkaia Teknologia ParkeaIkerbasque, Basque Foundation for Science Email author 

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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.


Ube3a Ubiquitin Angelman syndrome Autism Proteasome Rpn10