ATXN3 deubiquitinates polyUb-PARK2

Ataxin-3 (ATXN3) deubiquitinates the C-terminus of PARK2 (Parkin) (Winborn et al. 2008, Durcan et al. 2011). This promotes the degradation of PARK2. <br><br>An unstable CAG trinucleotide repeat expansion in the ATXN3 gene leads to elongation of the polyglutamine (polyQ) tract within the ATXN3 protein, and is believed to be the cause of Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3), the most common dominantly inherited form of ataxia (Martins et al. 2007). Both wild-type and polyQ-expanded ATXN3 can deubiquitinate PARK2, regardless of the lysine residue used to assemble poly-Ub chains. The polyQ-expanded ATXN3 deubiquitinates PARK2 more efficiently than wild-type ATXN3, but the mutant rather than the wild-type ATXN3 promoted the clearance of PARK2 via the autophagy pathway. This apparent contradiction may be due to increased removal of K27- and K29-linked Ub conjugates on PARK2 by the polyQ-expanded ATXN3; Ub conjugates linked in this manner to PARK2 may protect it from autophagic degradation (Durcan et al. 2011).

Ataxin-3（ATXN3）去泛素化PARK2（Parkin）的C端（Winborn等，2008年，Durcan等，2011年）。此过程促进了PARK2的降解。<br><br>ATXN3基因中不稳定的CAG三核苷酸重复扩张导致ATXN3蛋白中多谷氨酰胺（polyQ）序列的延长，并被认为导致Machado-Joseph病（MJD）或脊髓小脑性共济失调3型（SCA3），这是最常见的显性遗传性共济失调形式（Martins等，2007年）。无论是野生型还是polyQ扩大的ATXN3，均可去泛素化PARK2，而不论是使用哪种赖氨酸残基来组装多泛素链。polyQ扩大的ATXN3比野生型ATXN3更有效地去泛素化PARK2，但突变型而非野生型ATXN3通过自噬途径促进了PARK2的清除。这一看似矛盾的现象可能源于polyQ扩大的ATXN3增加了与PARK2结合的K27-和K29连接的泛素化共轭物的去除；以这种方式与PARK2结合的泛素化共轭物可能保护其免受自噬性降解（Durcan等，2011年）。