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Published online before print September 2, 2004

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0504300

Received for publication May 20, 2004.
Revised July 19, 2004.
Accepted for publication August 2, 2004.

Article

Stabilin-1 localizes to endosomes and the trans-Golgi network in human macrophages and interacts with GGA adaptors

Julia Kzhyshkowska ^*@, Alexei Gratchev ^*, Jan-Henning Martens ^*, Olga Pervushina ^*, Srinivas Mamidi ^*, Sophie Johansson , Kai Schledzewski ^*, Berit Hansen ^*, Xiangyuan He , Jordan Tang , Kazuhisa Nakayama , and Sergij Goerdt ^*

*Department of Dermatology, University Medical Centre Mannheim, Ruprecht-Karls University Heidelberg, Germany; Department of Medical Biochemistry and Microbiology, University of Uppsala, Sweden; Oklahoma Medical Research Foundation, Oklahoma City; and Graduate School of Pharmaceutical Sciences, Kyoto University, Japan

^@ To whom correspondence should be addressed. E-mail: julia.kzhyshkowska{at}haut.ma.uni-heidelberg.de.

	Abstract

Stabilin-1 and stabilin-2 constitute a novel family of fasciclin domain-containing hyaluronan receptor homologues recently described by us. Whereas stabilin-1 is expressed in sinusoidal endothelial cells and in macrophages in vivo, stabilin-2 is absent from the latter. In the present study, we analyzed the subcellular distribution of stabilin-1 in primary human macrophages. Using flow cytometry, expression of stabilin-1 was demonstrated on the surface of interleukin-4/dexamethasone-stimulated macrophages (M2). By immunofluorescense and confocal microscopy, we established that stabilin-1 is preferentially localized in early endosome antigen-1-positive early/sorting endosomes and in recycling endosomes identified by transferrin endocytosis. Association of stabilin-1 was infrequently seen with p62 lck ligand-positive late endosomes and with CD63-positive lysosomes but not in lysosome-associated membrane protein-1-positive lysosomes. Stabilin-1 was also found in the trans-Golgi network (TGN) but not in Golgi stack structures. Glutathione S-transferase pull-down assay revealed that the cytoplasmic tail of stabilin-1 but not stabilin-2 binds to recently discovered Golgi-localized, -ear-containing, adenosine 5`-diphosphate-ribosylation factor-binding (GGA) adaptors GGA1, GGA2, and GGA3 long, mediating traffic between Golgi and endosomal/lysosomal compartments. Stabilin-1 did not bind to GGA3 short, which lacks a part of the Vps27p/Hrs/STAM domain. Deletion of DDSLL and LL amino acid motifs resulted in decreased binding of stabilin-1 with GGAs. A small portion of stabilin-1 colocalized with GGA2 and GGA3 in the TGN in M2. Treatment with brefeldin A resulted in accumulation of stabilin-1 in the TGN. Our results suggest that stabilin-1 is involved in the GGA-mediated sorting processes at the interface of the biosynthetic and endosomal pathways; similarly to other GGA-interacting proteins, stabilin-1 may thus function in endocytic and secretory processes of human macrophages.

Key Words: receptor • endocytosis • traffic • fasciclin domain • sorting signal

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