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 I-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.
Canuel
Maryssa
M
Department of Anatomy and Cell Biology, McGill University, 3640 University Street, Strathcona Building, Room 1-1, Montreal, Que. H3A2BA, Canada.
Korkidakis
Ann
A
Konnyu
Kristin
K
Morales
Carlos R
CR
D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D019556:COS Cells; D002402:Cathepsin D / Q000378:metabolism*; D056655:Cathepsin H; D002403:Cathepsins / Q000378:metabolism*; D002522:Chlorocebus aethiops; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D008024:Ligands; D008247:Lysosomes / Q000201:enzymology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D017384:Sequence Deletion; D000099183:Sortilin
D033942:Adaptor Proteins, Vesicular Transport; D002402:Cathepsin D; D056655:Cathepsin H; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D008024:Ligands; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D017527:Receptor, IGF Type 2; D000099183:Sortilin