Ataxin-3 (ATXN3) has an N-terminal Josephin domain (JD) that is conserved within a family of around 4 ubiquitin proteases. ATXN3, the best studied, can bind long chains of lysine-63 (K63)-linked and K48-linked poly-ubiquitin (poly-Ub), but its activity is highest for ubiquitin chains with at least four molecules of ubiquitin. It preferentially cleaves linkages between ubiquitin molecules linked through K63 rather than K48 (Winborn et al. 2008). In effect this trims longer polyubiquitin chains down to approximately four residues (Burnett et al. 2003). The other three human JD-containing proteins also have demonstrated deubiquitinase (DUB) activity (Tzvetkov & Breuer 2007). In vitro ATXN3 kinetics are slow when compared to other well-studied deubiquitinating enzymes (Nicastro et al. 2010) but become much faster when ATXN3 is activated by VCP (Laco et al. 2012). JOSD1 partially localizes to the plasma membrane (Seki et al. 2013).