ARFRP1 functions upstream of ARL1 and ARL5 to coordinate recruitment of distinct tethering factors to the trans-Golgi network

Abstract

SNARE-mediated fusion of endosome-derived transport carriers with the trans-Golgi network (TGN) depends on the concerted action of two types of tethering factors: long coiled-coil tethers of the golgin family, and the heterotetrameric complex GARP. Whereas the golgins mediate long-distance capture of the carriers, GARP promotes assembly of the SNAREs. It remains to be determined, however, how the functions of these tethering factors are coordinated. Herein we report that the ARF-like (ARL) GTPase ARFRP1 functions upstream of two other ARL GTPases, ARL1 and ARL5, which in turn recruit golgins and GARP, respectively, to the TGN. We also show that this mechanism is essential for the delivery of retrograde cargos to the TGN. Our findings thus demonstrate that ARFRP1 is a master regulator of retrograde-carrier tethering to the TGN. The coordinated recruitment of distinct tethering factors by a bifurcated GTPase cascade may be paradigmatic of other vesicular fusion events within the cell.