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Published 29 March 2004. doi:10.1083/jcb.200311064
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 164, Number 7, 1065-1076
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Article

 Localization of the AP-3 adaptor complex defines a novel endosomal exit site for lysosomal membrane proteins

Andrew A. Peden1, Viola Oorschot2, Boris A. Hesser1, Cary D. Austin1, Richard H. Scheller1, and Judith Klumperman2

1 Genentech Inc., South San Francisco, CA 94080
2 Cell Microscopy Center, Department of Cell Biology and Institute for Biomembranes, University Medical Center Utrecht, 3584CX Utrecht, Netherlands

Address correspondence to J. Klumperman, Cell Microscopy Center, Department of Cell Biology, University Medical Center Utrecht, AZU RM G02.525, Heidelberglaan 100, 3584CX Utrecht, Netherlands. Tel.: 31-30-250-6550. Fax: 31-30-254-1797. email: j.klumperman{at}lab.azu.nl

The adaptor protein (AP) 3 adaptor complex has been implicated in the transport of lysosomal membrane proteins, but its precise site of action has remained controversial. Here, we show by immuno-electron microscopy that AP-3 is associated with budding profiles evolving from a tubular endosomal compartment that also exhibits budding profiles positive for AP-1. AP-3 colocalizes with clathrin, but to a lesser extent than does AP-1. The AP-3– and AP-1–bearing tubular compartments contain endocytosed transferrin, transferrin receptor, asialoglycoprotein receptor, and low amounts of the cation-independent mannose 6-phosphate receptor and the lysosome-associated membrane proteins (LAMPs) 1 and 2. Quantitative analysis revealed that of these distinct cargo proteins, only LAMP-1 and LAMP-2 are concentrated in the AP-3–positive membrane domains. Moreover, recycling of endocytosed LAMP-1 and CD63 back to the cell surface is greatly increased in AP-3–deficient cells. Based on these data, we propose that AP-3 defines a novel pathway by which lysosomal membrane proteins are transported from tubular sorting endosomes to lysosomes.

Key Words: AP-3 adaptor protein; TGN; endosomes; immuno-EM; clathrin

The online version of this article includes supplemental material.

Abbreviations used in this paper: AP, adaptor protein; ASGPR, asialoglycoprotein receptor; CI-MPR, cation-independent mannose 6-phosphate receptor; EE, early endosome; LAMP, lysosome-associated membrane protein; NRK, normal rat kidney; Tf, transferrin; Tf-biotin, biotinylated transferrin; TfR, transferrin receptor.


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