Golgi targeting of ARF-like GTPase Arl3p requires its Nα-acetylation and the integral membrane protein Sys1p

Setty, Subba Rao Gangi; Strochlic, Todd I.; Tong, Amy Hin-Yan; Boone, Charles; Burd, Christopher G.

doi:10.1038/ncb1121

Cited by 172 publications

(178 citation statements)

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“…The maturation process may effect this change in fusogenic potential by the recruitment or loss of specific components of the fusion machinery. Interestingly, other small four-transmembrane domain proteins, including Yip1p and Sys1p, are required for the recruitment of small GTPases to specific compartments (Yang et al, 1998;Behnia et al, 2004;Setty et al, 2004). Although we were unable to detect a physical association between the Vps55/68 complex and the endosomal Rab GTPase Vps21p, the presence of these proteins in the same phenotypic cluster suggests the Vps55/68 complex may interact transiently with Vps21p to fulfill a specific step in endosome maturation.…”

Section: The Vps55/68 Complex Is Required For Two Transport Steps Outcontrasting

confidence: 39%

Global Analysis of Yeast Endosomal Transport Identifies the Vps55/68 Sorting Complex

Schluter

Lam

Brumm

et al. 2008

MBoC

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Endosomal transport is critical for cellular processes ranging from receptor down-regulation and retroviral budding to the immune response. A full understanding of endosome sorting requires a comprehensive picture of the multiprotein complexes that orchestrate vesicle formation and fusion. Here, we use unsupervised, large-scale phenotypic analysis and a novel computational approach for the global identification of endosomal transport factors. This technique effectively identifies components of known and novel protein assemblies. We report the characterization of a previously undescribed endosome sorting complex that contains two well-conserved proteins with four predicted membrane-spanning domains. Vps55p and Vps68p form a complex that acts with or downstream of ESCRT function to regulate endosomal trafficking. Loss of Vps68p disrupts recycling to the TGN as well as onward trafficking to the vacuole without preventing the formation of lumenal vesicles within the MVB. Our results suggest the Vps55/68 complex mediates a novel, conserved step in the endosomal maturation process. INTRODUCTIONEndosomal protein sorting is a highly conserved cellular process that is required for receptor down-regulation, viral replication, and development (Katzmann et al., 2002;Morita and Sundquist, 2004). Much progress has been made in recent years in identifying distinct multiprotein complexes that regulate the fusion of primary endocytic vesicles, the maturation of an early endosome into a multivesicular body (MVB), and the recycling of proteins and lipids to other organelles (Gruenberg and Stenmark, 2004;Bonifacino and Rojas, 2006). The ESCRT-I, -II, and -III complexes (endosomal-sorting complex required for transport), which act in sequence to regulate the formation of internal vesicles at the MVB, play a central role in endosome biogenesis (Katzmann et al., 2002;Hurley and Emr, 2006). Other transport complexes regulate the targeting and fusion of endosomes or endosome-derived vesicles with other organelles (Bowers and Stevens, 2005;Bonifacino and Rojas, 2006).Many components of the endosomal-sorting machinery were first identified in yeast genetic screens for mutants that are defective in protein transport to the yeast vacuole, which requires functional endosomal sorting and recycling (Bowers and Stevens, 2005). Most of these components have a conserved role in endosome biogenesis in higher cells. Mammalian homologues have been identified for most if not all yeast ESCRT subunits (von Schwedler et al., 2003;Hurley and Emr, 2006), and at least some of the machinery that regulates recycling from the MVB is also well conserved. For example, the five-subunit retromer complex that mediates endosome-to-trans-Golgi network (TGN) transport in yeast is associated with tubular regions of the endosome in mammalian cells and mediates retrograde transport (Arighi et al., 2004;Seaman, 2004). In the past 20 years, classical genetic screens have identified more than 50 vacuole protein-sorting (VPS) genes (Bowers and Stevens, 2005). Surprisingly, ...

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Section: The Vps55/68 Complex Is Required For Two Transport Steps Outcontrasting

confidence: 39%

Global Analysis of Yeast Endosomal Transport Identifies the Vps55/68 Sorting Complex

Schluter

Lam

Brumm

et al. 2008

MBoC

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“…In contrast to other ARFs and ARLs, ARFRP1 can hydrolyze GTP in the absence of a GTPaseactivating protein and lacks the N-myristoylation site (glycine 2), which is required for membrane association (3). For the closest relative of ARFRP1, the yeast Arl3p protein, it was shown recently that membrane association is mediated via acetylation of the N-terminal methionine residue (4,5). ARFRP1 interacts with the Sec7 domain of the ARF-specific guanine nucleotide exchange factor cytohesin 1 in a GTP-dependent manner.…”

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confidence: 99%

ADP-ribosylation Factor-like GTPase ARFRP1 Is Required for Trans-Golgi to Plasma Membrane Trafficking of E-cadherin

Zahn

Jaschke

Weiske

et al. 2008

Journal of Biological Chemistry

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ADP-ribosylation factor-related protein 1 (ARFRP1) plays a specific role in Golgi function controlling recruitment of GRIP domain proteins and ARL1 to the trans-Golgi. Deletion of the mouse Arfrp1 gene causes embryonic lethality during early gastrulation, because epiblast cells detach from the ectodermal cell layer and do not differentiate to mesodermal tissue. Here we show that in Arfrp1 ؊/؊ embryos E-cadherin is mistargeted to intracellular compartments, whereas in control embryos it is present at the cell surface of trophectodermal and ectodermal cells. In enterocytes of intestine-specific Arfrp1 null mutants (Arfrp1), E-cadherin is associated with intracellular membranes, partially colocalizing with the cis-Golgi marker GM130 or with punctae close to the cell surface. In contrast, in control enterocytes E-cadherin is exclusively located in the lateral membranes. In addition, ARL1 is dislocated from Golgi membranes to the cytosol of Arfrp1 vil؊/؊ enterocytes. Depletion of endogenous ARFRP1 by RNA interference leads to a dislocation of E-cadherin from the cell surface in HeLa cells and to a reduced cell aggregation in Ltk ؊ Ecad cells. ARFRP1 was coimmunoprecipitated in a complex with E-cadherin, ␣-catenin, ␤-catenin, ␥-catenin, and p120 ctn from lysates of MadinDarby canine kidney cells stably expressing myc-ARFRP1. These data indicate that knock-out of Arfrp1 disrupts the trafficking of E-cadherin through the Golgi and suggest an essential role of the GTPase in trans-Golgi network function.

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“…Mutations in these complexes lead to a number of pleiotropic phenotypes, but in recent years, a growing number of these defects have been specifically linked to single protein substrates. For example, telomeric silencing, membrane trafficking, L-A viral assembly, and tropomyosin-actin interactions are mediated by the specific N-terminal acetylation of Orc1, Arl3, gag, and Tpm1, respectively (Tercero and Wickner, 1992;Singer and Shaw, 2003;Behnia et al, 2004;Geissenhoner et al, 2004;Setty et al, 2004). In many of these cases, the loss of acetylation reduces the affinity of these substrates for a partner protein, providing a detailed mechanistic explanation for the observed phenotype.…”

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confidence: 99%

The NatA Acetyltransferase Couples Sup35 Prion Complexes to the [PSI⁺] Phenotype

Pezza

Langseth

Yamamoto

et al. 2009

MBoC

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Protein-only (prion) epigenetic elements confer unique phenotypes by adopting alternate conformations that specify new traits. Given the conformational flexibility of prion proteins, protein-only inheritance requires efficient self-replication of the underlying conformation. To explore the cellular regulation of conformational self-replication and its phenotypic effects, we analyzed genetic interactions between [PSI ؉ ], a prion form of the S. cerevisiae Sup35 protein (Sup35 [PSI ؉ ] ), and the three N ␣ -acetyltransferases, NatA, NatB, and NatC, which collectively modify ϳ50% of yeast proteins. Although prion propagation proceeds normally in the absence of NatB or NatC, the [PSI ؉ ] phenotype is reversed in strains lacking NatA. Despite this change in phenotype, [PSI ؉ ] NatA mutants continue to propagate heritable Sup35 [PSI ؉ ] . This uncoupling of protein state and phenotype does not arise through a decrease in the number or activity of prion templates (propagons) or through an increase in soluble Sup35. Rather, NatA null strains are specifically impaired in establishing the translation termination defect that normally accompanies Sup35 incorporation into prion complexes. The NatA effect cannot be explained by the modification of known components of the [PSI ؉ ] prion cycle including Sup35; thus, novel acetylated cellular factors must act to establish and maintain the tight link between Sup35 [PSI ؉ ] complexes and their phenotypic effects. INTRODUCTIONThe transmission of phenotypes from one individual to another is a fundamental process in biology. Much of our understanding of these events arises from decades of study on nucleic acid metabolism, but new traits may also be passed between individuals without changes in nucleic acid content through a number of epigenetic mechanisms. One particularly intriguing example of such a process is the prion phenomenon, in which the activity of a protein is altered in a heritable way to transmit a new phenotype. How is such a feat accomplished? In 1967, Griffith proposed that some proteins, now known as prions (Prusiner, 1982), can adopt more than one stable form in vivo (Griffith, 1967). Since a protein's structure determines its function, two cells containing the same protein but in diffrent physical states will have distinct phenotypes. This protein-based process has been linked to a number of previously inexplicable events, including the development and spread of the transmissible spongiform encephalopathies in mammals (Prusiner, 1982) and the non-Mendelian inheritance of some traits in fungi (Wickner, 1994).Protein-based traits can only become transmissible, however, if the inherent structural flexibility of prion proteins can be constrained by regulatory mechanisms to create an epigenetic element. For example, if each newly synthesized prion polypeptide chain independently folded to a unique form, all cells would display the same phenotype, which would reflect the average of the accessible states. The appearance of distinct protein-based phenotypes suggests that ...

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Golgi targeting of ARF-like GTPase Arl3p requires its Nα-acetylation and the integral membrane protein Sys1p

Cited by 172 publications

References 32 publications

Global Analysis of Yeast Endosomal Transport Identifies the Vps55/68 Sorting Complex

Global Analysis of Yeast Endosomal Transport Identifies the Vps55/68 Sorting Complex

ADP-ribosylation Factor-like GTPase ARFRP1 Is Required for Trans-Golgi to Plasma Membrane Trafficking of E-cadherin

The NatA Acetyltransferase Couples Sup35 Prion Complexes to the [PSI⁺] Phenotype

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Golgi targeting of ARF-like GTPase Arl3p requires its Nα-acetylation and the integral membrane protein Sys1p

Cited by 172 publications

References 32 publications

Global Analysis of Yeast Endosomal Transport Identifies the Vps55/68 Sorting Complex

Global Analysis of Yeast Endosomal Transport Identifies the Vps55/68 Sorting Complex

ADP-ribosylation Factor-like GTPase ARFRP1 Is Required for Trans-Golgi to Plasma Membrane Trafficking of E-cadherin

The NatA Acetyltransferase Couples Sup35 Prion Complexes to the [PSI+] Phenotype

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The NatA Acetyltransferase Couples Sup35 Prion Complexes to the [PSI⁺] Phenotype