Small GTP-binding protein associated with Golgi cisternae

Goud, Bruno; Zahraoui, Ahmed; Tavitian, Armand; Saraste, Jaakko

doi:10.1038/345553a0

Cited by 344 publications

(238 citation statements)

References 29 publications

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“…However, with rab6 being enriched in trans-relative to cis-Golgi (Goud et al, 1990), such events would then contribute little to the total rab6-mediated recycling events, resulting in the trans-first scenario highlighted in this study.…”

Section: Rab6mentioning

confidence: 90%

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

Young

Stauber

Nery

et al. 2005

MBoC

104

126

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The small GTPase rab6A but not the isoform rab6A has previously been identified as a regulator of the COPIindependent 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. INTRODUCTIONAnterograde flow of material through the exocytic pathway is offset by the constant recycling of both proteins and lipids. This recycling helps to ensure that steady-state distributions of resident proteins are maintained within the pathway at the same time as keeping a lipid balance. Besides intra-Golgi recycling between cisternae (Hoe et al., 1995;Love et al., 1998;Lanoix et al., 1999;Lin et al., 1999), Golgi glycosylation enzymes also can recycle directly to the endoplasmic reticulum (ER). It is estimated that at least 5% of Golgi resident enzymes reside in the ER, at steady state (Pelletier et al., 2000). This pool constitutes recycled material originating from the Golgi apparatus (Cole et al., 1998;Storrie et al., 1998).The extent of ER recycling of Golgi resident membrane proteins is sufficient to allow for complete assembly of functional Golgi stacks. Thus, upon addition of nocodazole to depolymerize microtubules, the central and juxtanuclear Golgi apparatus relocates to the 100 or so peripheral ER exit sites scattered throughout the cell. This microtubule-independent relocation occurs in the absence of any detectable elements tracking outwards from the central Golgi apparatus. Rather, the Golgi apparatus undergoes a molecular deconstruction in the trans-to-cis-direction, i.e., resident glycosylation enzymes of the trans-cisternae/trans-Golgi network (TGN) relocate with faster kinetics than do enzymes of the medial-cisternae (Yang and Storrie, 1998). Enzymes seemingly enter the ER close to the microtubule organizing center (MTOC), diffuse through the ER, and then reemerge at peripheral ER exit sites. Here, Golgi stacks are then reassembled into discrete, yet fully functiona...

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Section: Rab6mentioning

confidence: 90%

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

Young

Stauber

Nery

et al. 2005

MBoC

104

126

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“…After 45 min, the protein became detectable in the Golgi apparatus A, C, and E) or B-Glyc-KDELGL (panel G) was bound to HeLa cells as described in Fig. 3 where it colocalized with Rab6, a GTPase associated with Golgi and TGN membranes (38,39) (Fig. 4, C and D).…”

Section: B-glyc-kdel and B-glyc-kdelgl Are Transported To The Er Via mentioning

confidence: 99%

Retrograde Transport of KDEL-bearing B-fragment of Shiga Toxin

Johannes¹,

Tenza

Antony

et al. 1997

Journal of Biological Chemistry

Self Cite

187

254

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To investigate retrograde transport along the biosynthetic/secretory pathway, we have constructed a recombinant Shiga toxin B-fragment carrying an N-glycosylation site and a KDEL retrieval motif at its carboxyl terminus (B-Glyc-KDEL). After incubation with HeLa cells, B-Glyc-KDEL was progressively glycosylated in the endoplasmic reticulum (ER) and remained stably associated with this compartment. B-fragment with a nonfunctional KDEL sequence (B-Glyc-KDELGL) was glycosylated with about the same kinetics as B-Glyc-KDEL but localized at steady state to the Golgi apparatus. Morphological studies showed that B-Glyc-KDEL was delivered from the plasma membrane, via endosomes and the cisternae of the Golgi apparatus, to the ER. Moreover, the addition of a sulfation site allowed us to show that B-Glyc-KDEL on transit to the ER entered the Golgi apparatus through the trans-Golgi network. Transport of B-Glyc-KDEL to the ER was slowed down by nocodazole, indicating that microtubules are important for the retrograde pathway. Our results document the existence of a continuous pathway from the plasma membrane to the endoplasmic reticulum via the Golgi apparatus and show that a fully folded exogenous protein arriving in the endoplasmic reticulum via this pathway can undergo N-glycosylation.

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“…As a result, the WTH3 gene was discovered. The gene product is homologous to the Rab6 and Rab6c genes that belong to the ras super family and encode small G proteins (Zahraoui et al, 1989;Goud et al, 1990;Echard et al, 1998Echard et al, , 2000Shan et al, 2000Shan et al, , 2002a. Similar to the Rab6s, WTH3 is a housekeeping gene and its product is capable of binding to GTP molecules (Tian et al, 2005b).…”

mentioning

confidence: 99%

WTH3 is a direct target of the p53 protein

Tian

Wang

2007

Br J Cancer

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Previous results showed that overexpression of the WTH3 gene in multidrug resistance (MDR) cells reduced MDR1 gene expression and converted their resistance to sensitivity to various anticancer drugs. The WTH3 gene promoter was found to be differentially regulated in paired MDR vs non-MDR MCF7 cells owing to epigenetic modifications and transcription factor modulations. To understand further the mechanisms that govern WTH3's differential expression, we uncovered a p53-binding site in its promoter, which indicated that WTH3 could be regulated by the p53 gene. This hypothesis was then tested by different strategies. The resulting data revealed that (1) the WTH3 promoter was upregulated by the p53 transgene in diverse host cells; (2) there was a correlation between WTH3 expression levels and p53 gene status in a cell line panel; (3) a WTH3 promoter region was directly targeted by the p53 protein in vitro and in vivo. In addition, overexpression of the WTH3 gene promoted the apoptotic phenotype in host cells. On the basis of these findings, we believe that the negative role played by the WTH3 gene in MDR development is through its proapoptotic potential that is regulated by multiple mechanisms at the transcription level, and one of these mechanisms is linked to the p53 gene.

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Small GTP-binding protein associated with Golgi cisternae

Cited by 344 publications

References 29 publications

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

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

Retrograde Transport of KDEL-bearing B-fragment of Shiga Toxin

WTH3 is a direct target of the p53 protein

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