The ARF-like GTPases Arl1p and Arl3p Act in a Pathway that Interacts with Vesicle-Tethering Factors at the Golgi Apparatus

Panić, B.; Whyte, James R.C.; Munro, Sean

doi:10.1016/s0960-9822(03)00091-5

Cited by 168 publications

(260 citation statements)

References 33 publications

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“…The two TGN golgins, p230 and golgin-97, depend on Arl1 for membrane recruitment (17)(18)(19)25). Our previous analyses showed that different cargoes are selectively packaged into different Golgi tubules, and that these tubules bud off to form transport carriers.…”

Section: Discussionmentioning

confidence: 99%

“…There are four human TGN golgins, namely p230/golgin-245, golgin-97, GCC185 and GCC88 (8)(9)(10)(11)(12)(13), which all belong to a subfamily of golgins characterized by a C-terminal GRIP domain (14)(15)(16). Recruitment of both p230/ golgin-245 (p230) and golgin-97 to the TGN is mediated through an interaction with the small G protein Arl1 (17)(18)(19)(20); however, these two golgins are localized to distinct membrane domains of the TGN (21). Distinct spatial segregation of p230 and golgin-97 is also reflected in their selective function, each being associated with TGN tubules bearing different cargo molecules.…”

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confidence: 99%

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A trans -Golgi network golgin is required for the regulated secretion of TNF in activated macrophages in vivo

Lieu

Lock

Hammond

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The transmembrane precursor of tumor necrosis factor-␣ (TNF) exits the trans-Golgi network (TGN) in tubular carriers for subsequent trafficking and delivery to the cell surface; however, the molecular machinery responsible for Golgi export is unknown. We previously reported that members of the TGN golgin family are associated with subdomains and tubules of the TGN. Here, we show that the TGN golgin, p230/golgin-245 (p230), is essential for intracellular trafficking and cell surface delivery of TNF in transfected HeLa cells and activated macrophages. Live-cell imaging revealed that TNF transport from the TGN is mediated selectively by tubules and carriers marked by p230. Significantly, LPS activation of macrophages resulted in a dramatic increase of p230-labeled tubules and carriers emerging from the TGN, indicating that macrophages up-regulate the transport pathway for TNF export. Depletion of p230 in LPS-stimulated macrophages reduced cell surface delivery of TNF by >10-fold compared with control cells. To determine whether p230 depletion blocked TNF secretion in vivo, we generated retrogenic mice expressing a microRNAvector to silence p230. Bone-marrow stem cells were transduced with recombinant retrovirus containing microRNA constructs and transplanted into irradiated recipients. LPS-activated peritoneal macrophages from p230 miRNA retrogenic mice were depleted of p230 and had dramatically reduced levels of cell surface TNF. Overall, these studies have identified p230 as a key regulator of TNF secretion and have shown that LPS activation of macrophages results in increased Golgi carriers for export. Also, we have demonstrated a previously undescribed approach to control cytokine secretion by the specific silencing of trafficking machinery. intracellular trafficking ͉ RNAi transgenic mice ͉ TNF secretion ͉ inflammation ͉ membrane transport T umor necrosis factor-␣ (TNF) is the main proinflammatory cytokine made and secreted by inflammatory macrophages. Early release of TNF in response to LPS or other inflammatory signals enhances the activation and recruitment of T cells and ensures robust innate and acquired immune responses (1). The excessive secretion of TNF is also a prevalent and clinically significant problem in acute inflammation and in chronic inflammatory disease (2). Anti-TNF treatments have shown success in the treatment of rheumatoid arthritis, inflammatory bowel disease, and other conditions (3). Now improved antiTNF strategies that may offer more constrained or cell type specific control of TNF secretion are being sought. This requires identification of molecular mediators of TNF secretion, particularly those that can be targeted to block TNF release.We have characterized the secretory pathway for TNF in activated macrophages and identified key organelles and components of the trafficking machinery whose expression or function is up-regulated by LPS to support cytokine secretion (4-6). Among these are members of the SNARE family of membrane fusion proteins required at different points along this ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

A trans -Golgi network golgin is required for the regulated secretion of TNF in activated macrophages in vivo

Lieu

Lock

Hammond

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…GARP interacts directly with small GTPases that localize to the TGN [Ypt6/Rab6 (12, 13) and Arl1 (14)], and in humans, GARP also interacts with SNARE proteins specific to the retrograde pathway (t-SNARE proteins syntaxin 6, syntaxin 16, and v-SNARE Vamp4) and may facilitate formation of the SNARE complex (2) at the TGN, the site of vesicle fusion. The SNARE interaction requires N-terminal regions in the Vps53 and Vps54 proteins (2).…”

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confidence: 99%

Structure of a C-terminal fragment of its Vps53 subunit suggests similarity of Golgi-associated retrograde protein (GARP) complex to a family of tethering complexes

Vasan

Hutagalung

Novick

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The Golgi-associated retrograde protein (GARP) complex is a membrane-tethering complex that functions in traffic from endosomes to the trans-Golgi network. Here we present the structure of a C-terminal fragment of the Vps53 subunit, important for binding endosome-derived vesicles, at a resolution of 2.9 Å. We show that the C terminus consists of two α-helical bundles arranged in tandem, and we identify a highly conserved surface patch, which may play a role in vesicle recognition. Mutations of the surface result in defects in membrane traffic. The fold of the Vps53 C terminus is strongly reminiscent of proteins that belong to three other tethering complexes—Dsl1, conserved oligomeric Golgi, and the exocyst—thought to share a common evolutionary origin. Thus, the structure of the Vps53 C terminus suggests that GARP belongs to this family of complexes.

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“…The transport was restored to almost complete level (96%) (lane 3) when the same amount of GST-GRIP was heat-denatured before addition, suggesting that the inhibition requires the intact conformation of the GRIP domain. When the conserved residue Y697, which is essential for interaction with Arl1 and for Golgi targeting (Barr, 1999;Kjer-Nielsen et al, 1999a;Munro and Nichols, 1999;Lu and Hong, 2003;Panic et al, 2003b), was mutated to Ala, the resultant fusion protein, GST-GRIP/Y697A (lane 5), exhibited little inhibition toward STxB transport relative to the control (lane 4). Furthermore, with increasing amounts of GST-GRIP added to the assay, the transport of STxB was correspondingly reduced to a plateau of ϳ20% ( Figure 1C), indicating that the inhibition is dose dependent.…”

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confidence: 99%

Autoantigen Golgin-97, an Effector of Arl1 GTPase, Participates in Traffic from the Endosome to theTrans-Golgi Network

Lü

Tai

Hong

2004

MBoC

162

147

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The precise cellular function of Arl1 and its effectors, the GRIP domain Golgins, is not resolved, despite our recent understanding that Arl1 regulates the membrane recruitment of these Golgins. In this report, we describe our functional study of Golgin-97. Using a Shiga toxin B fragment (STxB)-based in vitro transport assay, we demonstrated that Golgin-97 plays a role in transport from the endosome to the trans-Golgi network (TGN). The recombinant GRIP domain of Golgin-97 as well as antibodies against Golgin-97 inhibited the transport of STxB in vitro. Membrane-associated Golgin-97, but not its cytosolic pool, was required in the in vitro transport assay. The kinetic characterization of inhibition by anti-Golgin-97 antibody in comparison with anti-Syntaxin 16 antibody established that Golgin-97 acts before Syntaxin 16 in endosome-to-TGN transport. Knock down of Golgin-97 or Arl1 by their respective small interference RNAs (siRNAs) also significantly inhibited the transport of STxB to the Golgi in vivo. In siRNA-treated cells with reduced levels of Arl1, internalized STxB was instead distributed peripherally. Microinjection of Golgin-97 antibody led to the fragmentation of Golgi apparatus and the arrested transport to the Golgi of internalized Cholera toxin B fragment. We suggest that Golgin-97 may function as a tethering molecule in endosome-to-TGN retrograde traffic. INTRODUCTIONIn eukaryotic cells, different types of cargo (solutes, lipids, and membrane proteins, including receptors and their ligands) internalized from the plasma membrane follow several routes upon reaching the early/sorting endosome. They could recycle back to the plasma membrane directly via early/sorting endosome or indirectly via the recycling endosome, or travel further to the lysosome via the late endosome. Recently, there was evidence suggesting the existence of two retrograde transport pathways from endosomes to the trans-Golgi network (TGN) (Ghosh et al., 1998;Mallard et al., 1998;Mallet and Maxfield, 1999). One pathway, used by furin (Mallet and Maxfield, 1999) and mannose-6-phosphate receptor (M6PR) (Diaz and Pfeffer, 1998;Sincock et al., 2003), is from the late endosome to the TGN. The other one, used by TGN38 (Ghosh et al., 1998), Shiga Toxin B fragment (STxB) (Mallard et al., 1998) and likely GLUT4 (Shewan et al., 2003), proceeds via the early endosome (EE) and/or the recycling endosome (RE), without passing through late endosomes. In addition, the large cation-independent M6PR and the small cation-dependent MPR46 are recently shown to also use this EE/RE-TGN pathway, in addition to its well characterized late endosome-TGN route (Medigeshi and Schu, 2003;Lin et al., 2004). These endosome-TGN pathways could be used by other proteins such as P-selectin (Straley and Green, 2000), membrane-type matrix metalloproteinases (Kang et al., 2002;Zucker et al., 2002;Remacle et al., 2003; Wang et al., 2004a,b), copper transporters (Petris and Mercer, 1999;Petris et al., 2002), and VAMP4, a TGN SNARE (unpublished observations). In addition, ...

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The ARF-like GTPases Arl1p and Arl3p Act in a Pathway that Interacts with Vesicle-Tethering Factors at the Golgi Apparatus

Cited by 168 publications

References 33 publications

A trans -Golgi network golgin is required for the regulated secretion of TNF in activated macrophages in vivo

A trans -Golgi network golgin is required for the regulated secretion of TNF in activated macrophages in vivo

Structure of a C-terminal fragment of its Vps53 subunit suggests similarity of Golgi-associated retrograde protein (GARP) complex to a family of tethering complexes

Autoantigen Golgin-97, an Effector of Arl1 GTPase, Participates in Traffic from the Endosome to theTrans-Golgi Network

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