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Vol. 19, Issue 8, 3564-3575, August 2008

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Eps15 Mediates Vesicle Trafficking from the trans-Golgi Network via an Interaction with the Clathrin Adaptor AP-1

Mayo Clinic College of Medicine, Department of Biochemistry and Molecular Biology, and the Miles and Shirley Fiterman Center for Digestive Diseases, Rochester, MN 55905

Submitted October 3, 2007; Revised May 21, 2008; Accepted May 22, 2008
Monitoring Editor: Vivek Malhotra

Eps15 (EGFR pathway substrate clone 15) is well known for its role in clathrin-coated vesicle formation at the plasma membrane through interactions with other clathrin adaptor proteins such as AP-2. Interestingly, we observed that in addition to its plasma membrane localization, Eps15 is also present at the trans-Golgi network (TGN). Therefore, we predicted that Eps15 might associate with clathrin adaptor proteins at the TGN and thereby mediate the formation of Golgi-derived vesicles. Indeed, we have found that Eps15 and the TGN clathrin adaptor AP-1 coimmunoprecipitate from rat liver Golgi fractions. Furthermore, we have identified a 14-amino acid motif near the AP-2–binding domain of Eps15 that is required for binding to AP-1, but not AP-2. Disruption of the Eps15–AP-1 interaction via siRNA knockdown of AP-1 or expression of mutant Eps15 protein, which lacks a 14-amino acid motif representing the AP-1 binding site of Eps15, significantly reduced the exit of secretory proteins from the TGN. Together, these findings indicate that Eps15 plays an important role in clathrin-coated vesicle formation not only at the plasma membrane but also at the TGN during the secretory process.

Address correspondence to: Mark A. McNiven (mmcniven{at}mayo.edu)

Abbreviations used: AP, adaptor protein; BFA, brefeldin A; EH, Eps15 homology; ER, endoplasmic reticulum; Eps15, EGFR pathway substrate clone 15; GAE, -adaptin ear; GGA, Golgi-localized, -ear–containing, Arf-binding protein; M6PR, mannose 6-phosphate receptor; TGN, trans-Golgi network; UIM, ubiquitin-interacting motif; VSVG, vesicular stomatitis virus G protein.

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