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First published online 25 November 2008
doi: 10.1242/jcs.033522

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The adaptor complex AP-2 regulates post-endocytic trafficking through the non-clathrin Arf6-dependent endocytic pathway

¹ Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
² Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA

^* Author for correspondence (e-mail: mmc{at}mail.med.upenn.edu)

Accepted 1 September 2008

The ADP-ribosylation factor 6 (Arf6) GTPase functions as a key regulator of endocytic trafficking, participating in clathrin-independent endocytosis in most cell types. Unexpectedly, we found that siRNA-mediated depletion of clathrin or of adaptor protein 2 (AP-2)-complex subunits alters trafficking of Arf6 pathway cargo proteins, such as major histocompatibility complex class I (MHCI) and β1 integrin. Internalization of these cargoes from the plasma membrane was not affected in cells depleted of clathrin, but was modestly delayed in cells lacking AP-2. Furthermore, depletion of clathrin or AP-2 altered the intracellular distribution of MHCI and β1 integrin, inducing clustering in a perinuclear region. Despite this altered localization in both depleted populations, enhanced lysosomal targeting of MHCI was observed uniquely in cells that lack AP-2. Total levels of MHCI were modestly but consistently reduced in AP-2-depleted cells, and restored by the lysosomal inhibitor bafilomycin A. Furthermore, the half-life of surface-derived MHCI was reduced in AP-2-depleted cells. Consistent with enhanced degradative sorting, colocalization of Arf6 cargo with the late endosome and lysosome markers CD63 and Lamp1 was increased in cells depleted of AP-2 but not clathrin. These studies indicate a role for AP-2 in maintaining normal post-endocytic trafficking through the Arf6-regulated, non-clathrin pathway, and reveal pervasive effects of clathrin and AP-2 depletion on the endosomal and lysosomal system.

Key words: Endocytosis, Arf6, AP-2, Clathrin, MHCI, β1 integrin

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