Pheromone- and RSP5-dependent Ubiquitination of the G Protein β Subunit Ste4 in Yeast

Zhu, Ming; Torres, Matthew P.; Kelley, Joshua B.; Dohlman, Henrik G.; Wang, Yuqi

doi:10.1074/jbc.m111.254193

Cited by 15 publications

(13 citation statements)

References 52 publications

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“…Gα and Gβ may influence chemotropism by additional means. For instance, Gβ phosphorylation permits its monoubiquitylation, a modification that also influences its chemotropic function (Zhu et al, 2011). Another possible mean of control may be through Gα ubiquitylation (Wang et al, 2005), which is required for a normal morphogenetic response and controls its internalization and degradation through a mechanism partly distinct from receptor endocytosis (Dixit et al, 2014).…”

Section: Mechanisms Of Patch Stabilization Upon Pheromone Sensingmentioning

confidence: 99%

Molecular mechanisms of chemotropism and cell fusion in unicellular fungi

Martin

2019

Journal of Cell Science

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In all eukaryotic phyla, cell fusion is important for many aspects of life, from sexual reproduction to tissue formation. Fungal cells fuse during mating to form the zygote, and during vegetative growth to connect mycelia. Prior to fusion, cells first detect gradients of pheromonal chemoattractants that are released by their partner and polarize growth in their direction. Upon pairing, cells digest their cell wall at the site of contact and merge their plasma membrane. In this Review, I discuss recent work on the chemotropic response of the yeast models Saccharomyces cerevisiae and Schizosaccharomyces pombe, which has led to a novel model of gradient sensing: the cell builds a motile cortical polarized patch, which acts as site of communication where pheromones are released and sensed. Initial patch dynamics serve to correct its position and align it with the gradient from the partner cell. Furthermore, I highlight the transition from cell wall expansion during growth to cell wall digestion, which is imposed by physical and signaling changes owing to hyperpolarization that is induced by cell proximity. To conclude, I discuss mechanisms of membrane fusion, whose characterization remains a major challenge for the future.

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Section: Mechanisms Of Patch Stabilization Upon Pheromone Sensingmentioning

confidence: 99%

Molecular mechanisms of chemotropism and cell fusion in unicellular fungi

Martin

2019

Journal of Cell Science

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“…Thus, mono-and polyubiquitination represent important targeting signals, both of which lead to the eventual degradation of Gpa1. The yeast G␤ (Ste4) and G-protein-coupled receptor (Ste2) are likewise monoubiquitinated (35,36). In contrast to Gpa1, however, monoubiquitination of Ste4 does not lead to internalization and delivery to the vacuole.…”

Section: G␣ Regulation By Mono-and Polyubiquitination: Lessons From Ymentioning

confidence: 99%

“…In contrast to Gpa1, however, monoubiquitination of Ste4 does not lead to internalization and delivery to the vacuole. Rather monoubiquitination occurs in response to pheromone stimulation and promotes proper cell polarization and pheromone gradient detection (36).…”

Section: G␣ Regulation By Mono-and Polyubiquitination: Lessons From Ymentioning

confidence: 99%

Regulation of large and small G proteins by ubiquitination

Dohlman

Campbell

2019

Journal of Biological Chemistry

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Edited by Mike Shipston Many sensory and chemical signal inputs are transmitted by intracellular GTP-binding (G) proteins. G proteins make up two major subfamilies: "large" G proteins comprising three subunits and "small" G proteins, such as the proto-oncogene product RAS, which contains a single subunit. Members of both subfamilies are regulated by post-translational modifications, including lipidation, proteolysis, and carboxyl methylation. Emerging studies have shown that these proteins are also modified by ubiquitination. Much of our current understanding of this posttranslational modification comes from investigations of the large G-protein ␣ subunit from yeast (Gpa1) and the three RAS isotypes in humans, NRAS, KRAS, and HRAS. G␣ undergoes both mono-and polyubiquitination, and these modifications have distinct consequences for determining the sites and mechanisms of its degradation. Genetic and biochemical reconstitution studies have revealed the enzymes and binding partners required for addition and removal of ubiquitin, as well as the delivery and destruction of both the mono-and polyubiquitinated forms of the G protein. Complementary studies of RAS have identified multiple ubiquitination sites, each having distinct consequences for binding to regulatory proteins, shuttling to and from the plasma membrane, and degradation. Here, we review what is currently known about these two well-studied examples, Gpa1 and the human RAS proteins, that have revealed additional mechanisms of signal regulation and dysregulation relevant to human physiology. We also compare and contrast the effects of G-protein ubiquitination with other post-translational modifications of these proteins. A variety of sensory and chemical signals are detected by receptors at the cell surface. In many cases, these inputs are transmitted by intracellular GTP-binding proteins (Fig. 1). Generally speaking, large G proteins are activated by seven transmembrane segment receptors, also known as G-proteincoupled receptors (GPCRs). 3 When these receptors bind to an agonist ligand, the G-protein ␣ subunit releases GDP, binds to GTP, and dissociates from the G␤␥ subunit dimer. GTP-bound G␣, G␤␥, or both go on to activate intracellular effectors that transduce the signal. Similarly, many small G proteins are activated by growth factor receptors and their associated guanine nucleotide-exchange factors (GEFs). As with GPCRs, GEFs promote the exchange of GTP for GDP and subsequent activation of downstream effectors. For both large and small G proteins, signaling persists until GTP is converted to GDP, and this inactivation step is accelerated by binding to GTPase-activating proteins (GAPs). Thus, GEFs and GAPs work in opposition to one another to regulate the activity of their cognate G proteins, both large and small. Here, we review newer mechanisms of G-protein regulation by ubiquitination, with a focus on a large G protein from yeast and three small G proteins from humans: NRAS, KRAS, and HRAS. We compare and contrast the effects of ubiquitination with ...

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“…Hence, Ldb19, Rod1, and Rog3 cannot be involved in the reported Rsp5-dependent modification of Gpa1, because as we have documented here, loss of these ␣-arrestins makes cells more sensitive to pheromone action. Similarly, it has been noted that Ste4 (G␤) becomes ubiquitinylated in an Rsp5-dependent manner on Lys340, but the presence or absence of this modification does not affect the rate of turnover of Ste4 and, unlike loss of Ldb19, Rod1, and Rog3, does not affect the magnitude or duration of pheromone-induced Fus3 activation (148). Hence, Ldb19, Rod1, and Rog3 cannot negatively regulate pheromone responses by being responsible for mediating the reported Rsp5-dependent modification of Ste4.…”

Section: Figmentioning

confidence: 99%

Specific α-Arrestins Negatively Regulate Saccharomyces cerevisiae Pheromone Response by Down-Modulating the G-Protein-Coupled Receptor Ste2

Alvaro

O’Donnell

Prosser

et al. 2014

Molecular and Cellular Biology

159

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e G-protein-coupled receptors (GPCRs) are integral membrane proteins that initiate responses to extracellular stimuli by mediating ligand-dependent activation of cognate heterotrimeric G proteins. In yeast, occupancy of GPCR Ste2 by peptide pheromone ␣-factor initiates signaling by releasing a stimulatory G␤␥ complex (Ste4-Ste18) from its inhibitory G␣ subunit (Gpa1). Prolonged pathway stimulation is detrimental, and feedback mechanisms have evolved that act at the receptor level to limit the duration of signaling and stimulate recovery from pheromone-induced G 1 arrest, including upregulation of the expression of an ␣-factor-degrading protease (Bar1), a regulator of G-protein signaling protein (Sst2) that stimulates Gpa1-GTP hydrolysis, and Gpa1 itself. Ste2 is also downregulated by endocytosis, both constitutive and ligand induced. Ste2 internalization requires its phosphorylation and subsequent ubiquitinylation by membrane-localized protein kinases (Yck1 and Yck2) and a ubiquitin ligase (Rsp5). Here, we demonstrate that three different members of the ␣-arrestin family (Ldb19/Art1, Rod1/Art4, and Rog3/ Art7) contribute to Ste2 desensitization and internalization, and they do so by discrete mechanisms. We provide genetic and biochemical evidence that Ldb19 and Rod1 recruit Rsp5 to Ste2 via PPXY motifs in their C-terminal regions; in contrast, the arrestin fold domain at the N terminus of Rog3 is sufficient to promote adaptation. Finally, we show that Rod1 function requires calcineurin-dependent dephosphorylation.

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Pheromone- and RSP5-dependent Ubiquitination of the G Protein β Subunit Ste4 in Yeast

Cited by 15 publications

References 52 publications

Molecular mechanisms of chemotropism and cell fusion in unicellular fungi

Molecular mechanisms of chemotropism and cell fusion in unicellular fungi

Regulation of large and small G proteins by ubiquitination

Specific α-Arrestins Negatively Regulate Saccharomyces cerevisiae Pheromone Response by Down-Modulating the G-Protein-Coupled Receptor Ste2

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