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Vol. 16, Issue 1, 162-177, January 2005

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Regulation of Microtubule-dependent Recycling at the Trans-Golgi Network by Rab6A and Rab6A'

Joanne Young, Tobias Stauber, Elaine del Nery, Isabelle Vernos, Rainer Pepperkok ^* , and Tommy Nilsson ^*  

Cell Biology and Biophysics Programme, European Molecular Biology Laboratory, D-69117 Heidelberg, Germany

Submitted March 29, 2004; Accepted October 5, 2004
Monitoring Editor: Benjamin Glick

The small GTPase rab6A but not the isoform rab6A' has previously been identified as a regulator of the COPI-independent recycling route that carries Golgi-resident proteins and certain toxins from the Golgi to the endoplasmic reticulum (ER). The isoform rab6A' has been implicated in Golgi-to-endosomal recycling. Because rab6A but not A', binds rabkinesin6, this motor protein is proposed to mediate COPI-independent recycling. We show here that both rab6A and rab6A' GTP-restricted mutants promote, with similar efficiency, a microtubule-dependent recycling of Golgi resident glycosylation enzymes upon overexpression. Moreover, we used small interfering RNA mediated down-regulation of rab6A and A' expression and found that reduced levels of rab6 perturbs organization of the Golgi apparatus and delays Golgi-to-ER recycling. Rab6-directed Golgi-to-ER recycling seems to require functional dynactin, as overexpression of p50/dynamitin, or a C-terminal fragment of Bicaudal-D, both known to interact with dynactin inhibit recycling. We further present evidence that rab6-mediated recycling seems to be initiated from the trans-Golgi network. Together, this suggests that a recycling pathway operates at the level of the trans-Golgi linking directly to the ER. This pathway would be the preferred route for both toxins and resident Golgi proteins.

Abbreviations used: BicD, Bicaudal-D; CGN, the cis-Golgi network; EEA1, early endosomal antigen-1; ER, endoplasmic reticulum; GalNAc-T2, N-acetylgalactosaminyltransferase-2; GalT, -galactosyltransferase; GFP, green fluorescent protein; LAMP1, lysosomal associated membrane protein-1; Mann-II, 1,2-mannosidase II; MPR46, 46-kDa mannose-6-phosphate receptor; MTOC, microtubule organizing centre; p50, dynamitin; TfR, transferrin receptor; TGN, the trans-Golgi network; VTC, vesicular tubular carrier; -adaptin, adaptor protein-1 subunit .

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

^* These authors contributed equally to this study.

Present address: Department of Medical Biochemistry, Göteborg University, 413 90 Göteborg, Sweden.

Corresponding authors. E-mail addresses: pepperko{at}embl.de; tommy.nilsson{at}medkem.gu.se.

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