Golgi-to-phagosome transport of acid sphingomyelinase and prosaposin is mediated by sortilin.
Sortilin, also known as neurotensin receptor 3 (NTR3), is a transmembrane protein with a dual function. It acts as a receptor for neuromediators and growth factors at the plasma membrane, but it has also been implicated in binding and transport of some lysosomal proteins. However, the role of sortilin during phagosome maturation has not been investigated before. Here, we show that in macrophages, sortilin is mainly localized in the Golgi and transported to latex-bead phagosomes (LBPs). Using live-cell imaging and electron microscopy, we found that sortilin is delivered to LBPs in a manner that depends on its cytoplasmic tail. We also show that sortilin participates in the direct delivery of acid sphingomyelinase (ASM) and prosaposin (PS) to the phagosome, bypassing fusion with lysosomal compartments. Further analysis confirmed that ASM and PS are targeted to the phagosome by sortilin in a Brefeldin-A-sensitive pathway. Analysis of primary macrophages isolated from Sort1(-/-) mice indicated that the delivery of ASM and PS, but not pro-cathepsin D, to LBPs was severely impaired. We propose a pathway mediated by sortilin by which selected lysosomal proteins are transported to the phagosome along a Golgi-dependent route during the maturation of phagosomes.
Wähe
Anna
A
European Molecular Biology Laboratory, Postfach 102209, 69117 Heidelberg, Germany.
Kasmapour
Bahram
B
Schmaderer
Christoph
C
Liebl
David
D
Sandhoff
Konrad
K
Nykjaer
Anders
A
Griffiths
Gareth
G
Gutierrez
Maximiliano G
MG
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D020126:Brefeldin A / Q000494:pharmacology; D045744:Cell Line, Tumor; D005260:Female; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010587:Phagocytosis; D010588:Phagosomes / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D049231:Saposins / Q000378:metabolism*; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D000099183:Sortilin
D033942:Adaptor Proteins, Vesicular Transport; D020126:Brefeldin A; D049231:Saposins; D013108:Sphingomyelin Phosphodiesterase; D000099183:Sortilin; C483344:Psap protein, mouse