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A Family of ADP-Ribosylation Factor Effectors That Can Alter Membrane Transport Through the Trans-Golgi Annette L

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A Family of ADP-Ribosylation Factor Effectors That Can Alter Membrane Transport Through the Trans-Golgi Annette L Molecular Biology of the Cell Vol. 11, 1241–1255, April 2000 A Family of ADP-Ribosylation Factor Effectors That Can Alter Membrane Transport through the trans-Golgi Annette L. Boman,* Chun-jiang Zhang, Xinjun Zhu, and Richard A. Kahn† Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322-3050 Submitted October 29, 1999; Revised January 21, 2000; Accepted January 28, 2000 Monitoring Editor: Hugh R.B. Pelham A family of three structurally related proteins were cloned from human cDNA libraries by their ability to interact preferentially with the activated form of human ADP-ribosylation factor 3 (ARF3) in two-hybrid assays. The specific and GTP-dependent binding was later confirmed through direct protein binding of recombinant proteins. The three proteins share large (Ϸ300 residues) domains at their N termini that are 60–70% identical to each other and a shorter (73 residues) domain at their C termini with 70% homology to the C-terminal “ear” domain of ␥-adaptin. Although GGA1 is found predominantly as a soluble protein by cell fractionation, all three proteins were found to localize to the trans-Golgi network (TGN) by indirect immunofluorescence. The binding of GGAs to TGN was sensitive to brefeldin A, consistent with this being an ARF-dependent event. Thus, these proteins have been named Golgi-localizing, ␥-adaptin ear homology domain, ARF-binding proteins, or GGAs. The finding that overexpression of GGAs was sufficient to alter the distribution of markers of the TGN (TGN38 and mannose 6-phosphate receptors) led us to propose that GGAs are effectors for ARFs that function in the regulation of membrane traffic through the TGN. INTRODUCTION cases, ARF was found not to be required for the transport/ fusion activity but only for inhibition of the assay by the ADP-ribosylation factors (ARFs) are 21-kDa GTP-binding nonhydrolyzable GTP analogue GTP␥S (Gant and Wilson, proteins that constitute a subfamily of the Ras superfamily 1997; Happe and Weidman, 1998). Thus, an obligate role for (Donaldson and Klausner, 1994; for reviews, see Boman and ARF in any of these steps is uncertain. However, a model Kahn, 1995; Moss and Vaughan, 1998). Results from several that has emerged is that ARFs recruit multimeric coat com- laboratories have pointed to a central role for ARFs in reg- plexes to the sites of vesicle buds and play a regulatory role ulating some aspect of membrane traffic, particularly to and in vesicle formation. from the Golgi, and more recently from the trans-Golgi Six currently defined coat protein complexes are thought network (TGN) (Stamnes and Rothman, 1993; Traub et al., to be recruited to membranes by ARF or an ARF family 1993; Ooi et al., 1998; Hirst et al., 1999). ARFs were originally member. Two of these coat complexes are heptameric found to localize to the Golgi (Stearns et al., 1990b). Assays of (COP-I and COP-II) and four are tetramers (adaptin com- endoplasmic reticulum (ER)-Golgi (Balch et al., 1992), intra- plexes AP-1, AP-2, AP-3, and AP-4). COP-I–coated vesicles Golgi (Taylor et al., 1992), endosome fusion (Lenhard et al., function in the transport of vesicles between the Golgi and 1992), and nuclear vesicle fusion (Boman et al., 1992) were the intermediate compartment (Cosson et al., 1996; Gaynor used to define a role for ARF in each assay, and presumably and Emr, 1997). COP-II, whose recruitment to membranes in those transport processes. However, in several of these involves activation of the ARF homologue SAR1, mediates export from the ER (Barlowe et al., 1994). The four adaptin * Present address: Department of Biochemistry and Molecular complexes share structural relatedness between homolo- Biology, University of Minnesota, Duluth, MN 55812. gous subunits and are recruited to membranes in concert † Corresponding author. E-mail address: [email protected]. with ARFs. AP-1 is found associated with sites of protein Abbreviations used: ARF, ADP-ribosylation factor; BFA, brefel- export from the TGN and on TGN-derived vesicles (Stamnes din A; bp, base pairs; EST, expressed sequence tag; GAP, ␥ and Rothman, 1993; Traub et al., 1993; Hirst and Robinson, GTPase-activating protein; GGA, Golgi-localizing, -adaptin ear 1998). AP-2 associates with plasma membranes in an ARF- homology domain, ARF-binding protein; GST-GGA1(145–639), fusion protein consisting of GST and amino acid residues 145– sensitive manner (West et al., 1997) and is found on endo- 639 of GGA1; kb, kilobase; M6PR, mannose 6-phosphate recep- somes derived from the plasma membrane. AP-3 tor; NRK, normal rat kidney; TGN, trans-Golgi network; UTR, (Dell’Angelica et al., 1997; Simpson et al., 1997; Ooi et al., untranslated region. 1998) and AP-4 (Dell’Angelica et al., 1999; Hirst et al., 1999) © 2000 by The American Society for Cell Biology 1241 A.L. Boman et al. are involved in transport within the endosomal-lysosomal BamHI sites and into pBG4D at the BamHI site. In addition to system and in the transport of non-clathrin–coated vesicles wild-type ARF3, we also subcloned two mutant alleles of ARF, from the TGN, respectively. [Q71L]ARF3, a dominant activating mutant, and [N126I]ARF3, a Much of the early work on the role of ARF in coat protein dominant negative mutant. Any DNA amplified by PCR was se- recruitment was fueled by results with the macrolide anti- quenced to confirm that no errors were introduced by the polymer- ase. biotic brefeldin A (BFA) because of its remarkable ability in The expression of each ARF-BD fusion protein was confirmed by live cells to cause protein coats (e.g., COP-I [Donaldson et al., immunoblotting. Proteins in yeast lysates were resolved by electro- 1990] and AP-1 [Traub et al., 1993]) on the Golgi to rapidly phoresis on SDS-PAGE gels, transferred to nitrocellulose, and fall off and the uncoated Golgi membranes to fuse with the probed with either mAb 12CA5 against the hemagglutinin (HA) ER (Lippincott-Schwartz et al., 1989). BFA was shown to epitope incorporated at the C terminus of the BD or ARF3-specific inhibit an ARF-specific guanine nucleotide exchange factor polyclonal antibody R-1023 (Cavenagh et al., 1996). in crude membrane fractions (Helms and Rothman, 1992; Randazzo et al., 1993) and later directly on purified ARF Two-Hybrid Screen guanine nucleotide exchange factors (Peyroche et al., 1996, 1999; Mansour et al., 1999; Togawa et al., 1999). Thus, until Transformation of Y190 with a plasmid encoding the activated ARF another site of BFA action is defined, it is reasonable to mutant construct [Q71L]ARF3-BD yielded strain YAB324. This strain was transformed with each of two human cDNA libraries, a conclude that a protein whose localization is rapidly (within B-cell library in pACT (8 ϫ 105 transformants) and a kidney library seconds to a few minutes) and dramatically altered by BFA in pGAD10 (9 ϫ 105 transformants; Stratagene, La Jolla, CA), and addition to live cells lies downstream of an ARF-dependent transformants were selected for histidine auxotrophy on minimal step. medium lacking histidine and containing 25 mM 3-aminotriazole. It is evident from both genetic and biochemical studies in After reselection on 3-aminotriazole, colonies were assayed for yeast and mammalian cells that, in addition to their effects ␤-galactosidase activity, as described previously (Breeden and on membrane traffic, ARFs regulate other cellular processes Nasmyth, 1985). Filters were incubated at 30°C for 30 min to 3 h, and must do so through regulated interactions with a vari- with color scoring at regular intervals. Obvious blue color develop- ety of effectors, distinct from those involved in membrane ment within 3 h was considered positive. The [Q71L]ARF3-BD plasmid, carrying a gene conferring sensitivity to cycloheximide, traffic. In addition, it is not clear if the effects of ARF on was next lost by growth of potential positive strains on plates vesicular traffic are direct or only mediated by interactions containing cycloheximide. Only those strains that tested negative in with coat proteins. To identify novel effectors for activated the ␤-galactosidase assay after losing the ARF plasmid were inves- ARFs, we initiated a two-hybrid screen of human cDNA tigated further. These were then tested in two-hybrid assays in Y190 libraries with the use of a dominant activated mutant of strains carrying either lamin or cdk2 as partners to confirm the ARF3 ([Q71L]ARF3) as bait. Among the effectors identified specificity of the interaction with [Q71L]ARF3. As a final selection were a group of three proteins, termed GGA1, GGA2, and and to enrich for potential ARF effectors or GTPase-activating pro- GGA3 (for Golgi-localizing, ␥-adaptin ear homology do- teins (GAPs), each library plasmid was also transformed into Y190 main, ARF-binding proteins), that share extensive sequence carrying either the wild-type ARF3-BD construct, pAB155, or the negative dominant mutant [N126I]ARF3 construct, pABH3-3. Only identity and that include a region at the C terminus with those library inserts encoding proteins that interacted preferentially marked homology to an adaptin subunit. We describe the with the activated mutant of ARF3 were pursued. direct and GTP-dependent binding of ARF3 to GGA1 and Library plasmids were rescued from each positive strain and provide data from in vivo studies of cells overexpressing confirmed to be of library origin by restriction digestion analysis. GGA proteins that support a model in which GGAs act as Each library plasmid was then transformed into Y190 or YAB324 ARF-sensitive components in protein transport from the cells to test for two-hybrid activity alone or to confirm the positive TGN. reactivity with [Q71L]ARF3-BD, respectively. Library inserts in those plasmids encoding proteins that interacted less well with ARF3 than with the activated mutant were then sequenced in both MATERIALS AND METHODS directions by automated DNA sequencing.
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