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.
Department of Anatomy and Cell Biology, McGill University, 3640 University Street, Strathcona Building, Room 1-1, Montreal, Que. H3A2BA, Canada.
Maryssa
M
Canuel
Ann
A
Korkidakis
Kristin
K
Konnyu
Carlos R
CR
Morales
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