Ataxin-3 (ATXN3) is a ubiquitously-expressed deubiqutinating enzyme with important functions in the proteasomal protein degradation pathway and regulation of transcription.

ATXN3 interacts with RAD23A and RAD23B, multiubiquitin chain receptors involved in modulation of proteasomal degradation. RAD23 binds to Lysine-48-linked (K48) polyubiquitin chains, and with a lower affinity to K63-linked chains, in a length-dependent manner. RAD23 is proposed to bind simultaneously to the 26S proteasome and polyubiquitinated substrates, thereby assisting their delivery to the proteasome (Wang et al. 2000).

The C-terminus of ATXN3 contains a polyglutamine (PolyQ) region that, when mutationally expanded to over 52 glutamines, causes the protein to form aggregates that are a hallmark of the neurodegenerative disease spinocerebellar ataxia 3 (SCA3) (Kawaguchi et al. 1994, Evers et al. 2014).