Sortilin mediates the lysosomal targeting of cathepsins D and H

Delivery of soluble lysosomal proteins to the lysosomes is dependent primarily on the mannose 6-phosphate receptor (M6PR). However, in 1-cell disease (ICD), in which the M6PR pathway is non-functional, some soluble lysosomal proteins continue to traffic to the lysosomes. In this paper, we tested the hypothesis that cathepsins D and H, two soluble proteases that exhibit M6PR-independent trafficking, are targeted to the lysosomes by sortilin. Using a dominant-negative sortilin construct and small interfering RNA (siRNA) we demonstrated that while cathepsin D transport is partially dependent upon sortilin, cathepsin H requires exclusively sortilin for its transport to the lysosomes. Our results suggest that sortilin functions as an alternative sorting receptor to the M6PR for these soluble hydrolases. (C) 2008 Elsevier Inc. All rights reserved.