Parkin and mitochondrial quality control: toward assembling the puzzle

• Parkin is a RBR E3 ubiquitin ligase that can mediate degradative and nondegradative ubiquitination.
• Parkin has been linked to autosomal-recessive Parkinsonism but also plays a role in innate immunity.
• Parkin acts in concert with PINK1 to mediate removal of damaged mitochondria via mitophagy.
• The prosurvival activity of parkin requires NEMO ubiquitination and NF-κB signaling.

Parkin is an E3 ubiquitin ligase associated with autosomal-recessive Parkinsonism. Moreover, parkin inactivation has been found in sporadic Parkinson's disease (PD), suggesting a wider pathogenic impact than initially predicted. Beyond its role in PD, parkin has also been implicated in innate immune responses. Since its discovery, mounting evidence indicates that parkin can mediate degradative as well as nondegradative ubiquitination. Here we review recent insights into the structure of parkin, the mechanism of its E3 ligase activity, and its functional versatility in an attempt to merge controversial aspects into a more comprehensive picture of this multifaceted E3 ubiquitin ligase.