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Molecular and Cellular Biology, October 2009, p. 5251-5263, Vol. 29, No. 19
0270-7306/09/$08.00+0     doi:10.1128/MCB.00495-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Dual Roles of the Mammalian GARP Complex in Tethering and SNARE Complex Assembly at the trans-Golgi Network{triangledown}

F. Javier Pérez-Victoria and Juan S. Bonifacino*

Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892

Received 15 April 2009/ Returned for modification 8 May 2009/ Accepted 8 July 2009

Tethering factors and SNAREs control the last two steps of vesicular trafficking: the initial interaction and the fusion, respectively, of transport vesicles with target membranes. The Golgi-associated retrograde protein (GARP) complex regulates retrograde transport from endosomes to the trans-Golgi network (TGN). Although GARP has been proposed to function as a tethering factor at the TGN, direct evidence for such a role is still lacking. Herein we report novel and specific interactions of the mammalian GARP complex with SNAREs that participate in endosome-to-TGN transport, namely, syntaxin 6, syntaxin 16, and Vamp4. These interactions depend on the N-terminal regions of Vps53 and Vps54 and the SNARE motif of the SNAREs. We show that GARP functions upstream of the SNAREs, regulating their localization and assembly into SNARE complexes. However, interactions of GARP with SNAREs are insufficient to promote retrograde transport, because deletion of the C-terminal region of Vps53 precludes GARP function without affecting GARP-SNARE interactions. Finally, we present in vitro data consistent with a tethering role for GARP, which is disrupted by deletion of the Vps53 C-terminal region. These findings indicate that GARP orchestrates retrograde transport from endosomes to the TGN by promoting vesicle tethering and assembly of SNARE complexes in consecutive, independent steps.

* Corresponding author. Mailing address: Cell Biology and Metabolism Program, NICHD, Building 18T/Room 101, NIH, Bethesda, MD 20892. Phone: (301) 496-6368. Fax: (301) 402-0078. E-mail: juan{at}helix.nih.gov

{triangledown} Published ahead of print on 20 July 2009.

Molecular and Cellular Biology, October 2009, p. 5251-5263, Vol. 29, No. 19
0270-7306/09/$08.00+0     doi:10.1128/MCB.00495-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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