Vac8p, an Armadillo Repeat Protein, Coordinates Vacuole Inheritance With Multiple Vacuolar Processes

Tang, Fusheng; Peng, Yutian; Nau, Johnathan J.; Kauffman, Emily J.; Weisman, Lois S.

doi:10.1111/j.1600-0854.2006.00458.x

Cited by 54 publications

(61 citation statements)

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“…11,28 It is not known how the cellular pool of Vac8p is apportioned among its various roles, though recent evidence suggests that Vac8p becomes compartmentalized into distinct vacuole subdomains through interactions with its less-abundant binding partners. 26 Because some of these proteins bind to overlapping segments of the ARM domain, their binding is likely to be mutually exclusive. 26 Indeed, the ectopic overexpression of Nvj1p causes defects in vacuole morphology and vacuole inheritance, presumably by out-competing Vac17p and sequestering Vac8p.…”

Section: Vac8p: a Binding Scaffold With Multiple Roles In Vacuole Phymentioning

confidence: 99%

“…26 Because some of these proteins bind to overlapping segments of the ARM domain, their binding is likely to be mutually exclusive. 26 Indeed, the ectopic overexpression of Nvj1p causes defects in vacuole morphology and vacuole inheritance, presumably by out-competing Vac17p and sequestering Vac8p. 11 Since other Armadillo-repeat proteins such as importin-a contain cis domains that regulate partner binding and dissociation reactions, it will be interesting to learn if similar mechanisms control Vac8p functions.…”

Section: Vac8p: a Binding Scaffold With Multiple Roles In Vacuole Phymentioning

confidence: 99%

“…Repeats 2-6 and 10-11 are required for interactions with Nvj1p. 26 Vac8p has other partners, including Vac17p, a component of the actin-based vacuole inheritance apparatus (reviewed in ref. 27), and Atg13p, which functions in the Cvt pathway and in macroautophagy.…”

Section: Vac8p: a Binding Scaffold With Multiple Roles In Vacuole Phymentioning

confidence: 99%

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Nucleus-Vacuole Junctions and Piecemeal Microautophagy of the Nucleus inS. cerevisiae

Kvam

Goldfarb²

2007

Autophagy

113

117

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Previously published online as an AcKnowlEDGEmEntSWe wish to thank past and present lab members who have contributed their ideas and technical assistance to this project, especially Jonathan Millen who made comments on this manuscript, and to our many helpful and supportive colleagues in the autophagy research community. This study was supported by grants from the National Science Foundation and National Institutes of Health. AbStrActVarious modes of autophagy conspire to degrade virtually every compartment of the eukaryotic cell. In Saccharomyces cerevisiae, a process called "piecemeal microautophagy of the nucleus" (PMN) even pinches off and degrades nonessential portions of the nucleus. PMN is a constitutive process induced to high levels by starvation or rapamycin, an inhibitor of TOR kinase. PMN occurs at nucleus-vacuole (NV) junctions, which are Velcro-like patches formed by interactions between the vacuole membrane protein Vac8p and the outer-nuclear-membrane protein Nvj1p. In response to nutrient depletion, Nvj1p increasingly binds and sequesters two proteins with roles in lipid metabolism, Osh1p and Tsc13p. Tsc13p is required for the normal biogenesis of PMN vesicles. The sequestration of Osh1p by Nvj1p likely serves to negatively regulate the trafficking of tryptophan permease(s) to the plasma membrane. Thus, NV junctions and PMN orchestrate novel and sophisticated responses to nutrient limitation.

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Section: Vac8p: a Binding Scaffold With Multiple Roles In Vacuole Phymentioning

confidence: 99%

Section: Vac8p: a Binding Scaffold With Multiple Roles In Vacuole Phymentioning

confidence: 99%

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Nucleus-Vacuole Junctions and Piecemeal Microautophagy of the Nucleus inS. cerevisiae

Kvam

Goldfarb²

2007

Autophagy

113

117

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“…Likewise, degradation of Vac17p is required for the termination of vacuole inheritance and the detachment of Myo2p from the vacuole membrane . Vac8p binds directly to Vac17p and attaches to the vacuole membrane via myristoylation and palmitoylation (Wang et al, 1998;Peng et al, 2006;Tang et al, 2006). Although the regulation of VAC17 contributes to the control of vacuole inheritance, other members of the myosin-V transport complex are also potential targets for the regulation of vacuole movement.…”

Section: Introductionmentioning

confidence: 99%

PTC1Is Required for Vacuole Inheritance and Promotes the Association of the Myosin-V Vacuole-specific Receptor Complex

Jin

Eves

Tang

et al. 2009

MBoC

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Organelle inheritance occurs during cell division. In Saccharomyces cerevisiae, inheritance of the vacuole, and the distribution of mitochondria and cortical endoplasmic reticulum are regulated by Ptc1p, a type 2C protein phosphatase. Here we show that PTC1/VAC10 controls the distribution of additional cargoes moved by a myosin-V motor. These include peroxisomes, secretory vesicles, cargoes of Myo2p, and ASH1 mRNA, a cargo of Myo4p. We find that Ptc1p is required for the proper distribution of both Myo2p and Myo4p. Surprisingly, PTC1 is also required to maintain the steady-state levels of organelle-specific receptors, including Vac17p, Inp2p, and Mmr1p, which attach Myo2p to the vacuole, peroxisomes, and mitochondria, respectively. Furthermore, Vac17p fused to the cargo-binding domain of Myo2p suppressed the vacuole inheritance defect in ptc1⌬ cells. These findings suggest that PTC1 promotes the association of myosin-V with its organelle-specific adaptor proteins. Moreover, these observations suggest that despite the existence of organelle-specific receptors, there is a higher order regulation that coordinates the movement of diverse cellular components. INTRODUCTIONDuring each cell cycle, cytoplasmic organelles are actively distributed between dividing cells to maintain organelle copy number and volume. The yeast Saccharomyces cerevisiae is an excellent model system for studying the spatial and temporal control of organelle inheritance. In yeast, several organelles are transmitted from mother to daughter cells. These include the vacuole, mitochondria, the endoplasmic reticulum (ER), late-Golgi elements and peroxisomes (reviewed in Weisman, 2006).Early in the cell cycle, a portion of each organelle is transported into the emerging bud. The polarized transport of most organelles from the mother to the bud is an active process that requires the actin cytoskeleton, myosin-V motors, and receptor proteins, which physically connect the motor to organelle cargoes (Beach et al., 2000;Yin et al., 2000;Boldogh et al., 2001;Barr, 2002;Bretscher, 2003;Du et al., 2004;Fagarasanu et al., 2006bFagarasanu et al., , 2007Weisman, 2006). Thus, formation of a complex between the motor and receptor protein is important for polarized organelle transport.Similar to yeast, in vertebrates, myosin-V motors move cargoes along the actin cytoskeleton. The best studied cargo of vertebrate myosin-V are melanosomes, which are moved in melanocytes by myosin-Va. Melanosomes attach to myosin-Va through Rab27a and melanophilin (Fukuda and Kuroda, 2002;Wu et al., 2002). Rab27a, through geranylgeranylation, attaches to the melanosome membrane, and melanophilin connects myosin-Va and Rab27a. Myosin-V-based intracellular movement has been analyzed in many other eukaryotes, including frogs, fish, mammals, and plants; plant myosin-XI is the functional homologue of yeast and vertebrate myosin-V ( Kinkema and Schiefelbein, 1994;Provance and Mercer, 1999;Tuma and Gelfand, 1999;Desnos et al., 2007;Li and Nebenfuhr, 2007;Sheets et al., 2007;Shimmen, 2007).Ge...

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“…The S. cerevisiae protein Vac8 is also palmitoylated at cysteines that are just downstream of its N-myristoylated glycine (18). Vac8 is a scaffolding protein consisting primarily of 11 armadillo repeats involved in protein-protein interactions (19,20). Located at the vacuolar limiting membrane, Vac8 is involved in several membrane-mediated events, including vacuolar fusion, vacuolar inheritance, cytoplasm-tovacuole targeting, and nuclear autophagy (18,(21)(22)(23)(24).…”

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confidence: 99%

Molecular Recognition of the Palmitoylation Substrate Vac8 by Its Palmitoyltransferase Pfa3

Nadolski¹,

Linder

2009

Journal of Biological Chemistry

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Palmitoylation of the yeast vacuolar protein Vac8 is important for its role in membrane-mediated events such as vacuole fusion. It has been established both in vivo and in vitro that Vac8 is palmitoylated by the Asp-His-His-Cys (DHHC) protein Pfa3. However, the determinants of Vac8 critical for recognition by Pfa3 have yet to be elucidated. This is of particular importance because of the lack of a consensus sequence for palmitoylation. Here we show that Pfa3 was capable of palmitoylating each of the three N-terminal cysteines of Vac8 and that this reaction was most efficient when Vac8 is N-myristoylated. Additionally, when we analyzed the Src homology 4 (SH4) domain of Vac8 independent of the rest of the protein, palmitoylation by Pfa3 still occurred. However, the specificity of palmitoylation seen for the full-length protein was lost, and the SH4 domain was palmitoylated by all five of the yeast DHHC proteins tested. These data suggested that a region of the protein C-terminal to the SH4 domain was important for conferring specificity of palmitoylation. This was confirmed by use of a chimeric protein in which the SH4 domain of Vac8 was swapped for that of Meh1, another palmitoylated and N-myristoylated protein in yeast. In this case we saw specificity mimic that of wild type Vac8. Competition experiments revealed that the 11th armadillo repeat of Vac8 is an important element for recognition by Pfa3. This demonstrates that regions distant from the palmitoylated cysteines are important for recognition by DHHC proteins.S-Palmitoylation (hereafter referred to as palmitoylation) is a widespread post-translational modification in which the fatty acid palmitate (16:0) is attached to a cysteine residue via a thioester linkage. Palmitate can be released from a cysteine by hydrolysis of the thioester linkage; thus palmitoylation is a reversible modification. Numerous eukaryotic proteins are palmitoylated, and substrates include both peripheral and transmembrane domain proteins. The functional consequences of palmitoylation are diverse. Membrane association, protein stability, and protein trafficking are among the properties that can be modulated by the palmitoylation status of a protein (reviewed in 1, 2).The enzymes responsible for palmitoylation have only recently been identified. The first protein acyltransferases (PATs) 3 discovered were Erf2 and Akr1 in yeast, which palmitoylate Ras2 and Yck2, respectively (3, 4). Both Erf2 and Akr1 are transmembrane proteins with an Asp-His-(His/Tyr)-Cys (DHHC) motif embedded in a cysteine-rich domain (CRD). Homology with this domain has identified five additional DHHC proteins in Saccharomyces cerevisiae. These seven proteins account for the bulk of palmitoylating activity in the cell (5).To date 23 DHHC proteins have been identified in mammals (6). As the field has progressed DHHC proteins have been linked to the regulation of neurotransmission (7-9), nitric oxide release (10), and cell-cell contacts (11). Palmitoylation of Huntingtin by HIP14 (DHHC17) plays a protective role in ...

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Vac8p, an Armadillo Repeat Protein, Coordinates Vacuole Inheritance With Multiple Vacuolar Processes

Cited by 54 publications

References 48 publications

Nucleus-Vacuole Junctions and Piecemeal Microautophagy of the Nucleus inS. cerevisiae

Nucleus-Vacuole Junctions and Piecemeal Microautophagy of the Nucleus inS. cerevisiae

PTC1Is Required for Vacuole Inheritance and Promotes the Association of the Myosin-V Vacuole-specific Receptor Complex

Molecular Recognition of the Palmitoylation Substrate Vac8 by Its Palmitoyltransferase Pfa3

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