RNF13 is a novel interactor of iduronate 2-sulfatase that modifies its glycosylation and maturation

Mucopolysaccharidosis type II, also known as Hunter syndrome, is a rare and fatal disease caused by mutations in the iduronate 2-sulfatase (IDS) encoding gene. The enzymatically inactive variant proteins lead to pathological accumulation of glycosaminoglycans in the lysosomes, causing dysfunction in multiple organs. IDS is expressed as a precursor protein, and its processing and lysosomal targeting are crucial for proper enzymatic activity. However, IDS intracellular dynamic is poorly understood and a better understanding of its processing mechanisms would benefit the development of new therapeutic strategies. AlphaFold 3 predicted an interaction between IDS and the E3 ubiquitin ligase RNF13. Co-immunoprecipitation assays confirm this interaction and further show that RNF13 interacts preferentially with a predominantly underglycosylated immature form of IDS, resulting in altered IDS glycosylation and maturation. The results demonstrate that IDS glycosylation site Asn246 is important for lysosomal targeting, although its glycosylation is not altered by RNF13. This study also unravels that RNF13 forms a heterodimer with the E3 ubiquitin ligase RNF167 that modify both RNF13 and RNF167 lysosomal trafficking. In addition, the heterodimer interacts and alters IDS differently than RNF13 or RNF167 alone. RNF13 catalytic E3 ligase activity is required to generate an underglycosylated form, but not that of RNF167. This study exposes that the proteasome rapidly degrades IDS underglycosylated forms, and RNF13 exerts a protective effect. Overall, this study reveals a novel and dual role of RNF13 on IDS maturation and degradation, providing mechanistic insights into IDS trafficking.