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Vol. 19, Issue 5, 1942-1951, May 2008

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Protein Networks Supporting AP-3 Function in Targeting Lysosomal Membrane Proteins

Thorsten Baust^*,, Mihaela Anitei^*,, Cornelia Czupalla^*,, Iryna Parshyna^*, Line Bourel, Christoph Thiele, Eberhard Krause^||, and Bernard Hoflack^*

*Biotechnological Center, Dresden University of Technology, 01307 Dresden, Germany; Faculté de Pharmacie de Lille, Laboratoire de Chimie, BP 83 59006 Lille Cedex, France; Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany; and ^||Institute of Molecular Pharmacology, 10 13125, Berlin, Germany

Submitted February 1, 2008; Revised February 7, 2008; Accepted February 12, 2008
Monitoring Editor: Sandra Schmid

The AP-3 adaptor complex targets selected transmembrane proteins to lysosomes and lysosome-related organelles. We reconstituted its preferred interaction with liposomes containing the ADP ribosylation factor (ARF)-1 guanosine triphosphatase (GTPase), specific cargo tails, and phosphatidylinositol-3 phosphate, and then we performed a proteomic screen to identify new proteins supporting its sorting function. We identified 30 proteins belonging to three networks regulating either AP-3 coat assembly or septin polymerization or Rab7-dependent lysosomal transport. RNA interference shows that, among these proteins, the ARF-1 exchange factor brefeldin A-inhibited exchange factor 1, the ARF-1 GTPase-activating protein 1, the Cdc42-interacting Cdc42 effector protein 4, an effector of septin-polymerizing GTPases, and the phosphatidylinositol-3 kinase IIIC3 are key components regulating the targeting of lysosomal membrane proteins to lysosomes in vivo. This analysis reveals that these proteins, together with AP-3, play an essential role in protein sorting at early endosomes, thereby regulating the integrity of these organelles.

These authors contributed equally to this work.

Address correspondence to: Bernard Hoflack (bernard.hoflack{at}biotec.tu-dresden.de)