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Vol. 19, Issue 6, 2650-2660, June 2008

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Redundant Roles of BIG2 and BIG1, Guanine-Nucleotide Exchange Factors for ADP-Ribosylation Factors in Membrane Traffic between the trans-Golgi Network and Endosomes

Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan

Submitted October 23, 2007; Revised March 19, 2008; Accepted April 3, 2008
Monitoring Editor: Akihiko Nakano

BIG2 and BIG1 are closely related guanine-nucleotide exchange factors (GEFs) for ADP-ribosylation factors (ARFs) and are involved in the regulation of membrane traffic through activating ARFs and recruiting coat protein complexes, such as the COPI complex and the AP-1 clathrin adaptor complex. Although both ARF-GEFs are associated mainly with the trans-Golgi network (TGN) and BIG2 is also associated with recycling endosomes, it is unclear whether BIG2 and BIG1 share some roles in membrane traffic. We here show that knockdown of both BIG2 and BIG1 by RNAi causes mislocalization of a subset of proteins associated with the TGN and recycling endosomes and blocks retrograde transport of furin from late endosomes to the TGN. Similar mislocalization and protein transport block, including furin, were observed in cells depleted of AP-1. Taken together with previous reports, these observations indicate that BIG2 and BIG1 play redundant roles in trafficking between the TGN and endosomes that involves the AP-1 complex.

* These authors contributed equally to this work.

Address correspondence to: Kazuhisa Nakayama (kazunaka{at}pharm.kyoto-u.ac.jp)

Abbreviations used: ARF, ADP-ribosylation factor; HRP, horseradish peroxidase; GEF, guanine nucleotide exchange factor; PACS, phosphofurin acidic cluster sorting protein; TGN, trans-Golgi network; TfnR, transferrin receptor; VSVG, vesicular stomatitis virus G protein.