The Small Yeast GTPase Rho5 and Its Dimeric GEF Dck1/Lmo1 Respond to Glucose Starvation

Schmitz, Hans‐Peter; Jendretzki, Arne; Sterk, Carolin; Heinisch, Jürgen J.

doi:10.3390/ijms19082186

Cited by 16 publications

(12 citation statements)

References 58 publications

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“…As expected, neither allele impaired growth in the absence of oxidative stress. Next, we used the previously observed synthetic lethality of rho5 and sch9 deletions to test the in vivo function of our mutant alleles [15]. Whereas the rho5 deletion did not produce any viable progeny in a sch9 background, the constitutively active RHO5 G12V variant produced small colonies typical of RHO5 sch9 segregants (Figure 2B).…”

Section: Resultsmentioning

confidence: 97%

“…All three components of the putative trimeric Dck1-Lmo1-Rho5 (DLR) complex rapidly translocate from the cell periphery to mitochondria under such stress conditions, followed by mitophagy and cell death [14]. The translocation of Rho5 occurs only in the presence of both Dck1 and Lmo1 and is also triggered by glucose starvation, thus linking the DLR complex to nutrient signaling [15].…”

Section: Introductionmentioning

confidence: 99%

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Analysis of Functional Domains in Rho5, the Yeast Homolog of Human Rac1 GTPase, in Oxidative Stress Response

Sterk

Gräber

Schmitz

et al. 2019

IJMS

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The small GTPase Rho5 of Saccharomyces cerevisiae is required for proper regulation of different signaling pathways, which includes the response to cell wall, osmotic, nutrient, and oxidative stress. We here show that proper in vivo function and intracellular distribution of Rho5 depends on its hypervariable region at the carboxyterminal end, which includes the CAAX box for lipid modification, a preceding polybasic region (PBR) carrying a serine residue, and a 98 amino acid–specific insertion only present in Rho5 of S. cerevisiae but not in its human homolog Rac1. Results from trapping GFP-Rho5 variants to the mitochondrial surface suggest that the GTPase needs to be activated at the plasma membrane prior to its translocation to mitochondria in order to fulfil its role in oxidative stress response. These findings are supported by heterologous expression of a codon-optimized human RAC1 gene, which can only complement a yeast rho5 deletion in a chimeric fusion with RHO5 sequences that restore the correct spatiotemporal distribution of the encoded protein.

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Section: Resultsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Analysis of Functional Domains in Rho5, the Yeast Homolog of Human Rac1 GTPase, in Oxidative Stress Response

Sterk

Gräber

Schmitz

et al. 2019

IJMS

Self Cite

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“…A large number of studies have shown that glucose metabolism can regulate cell death in variety of cell types (Gottlob et al 2001; Zhao et al 2008a; Zhao et al 2008b; Rathmell et al 2003; Matsuura et al 2016). Interestingly, a recent study suggests that Rho5 relocates from the plasma membrane to mitochondria upon glucose starvation (Schmitz et al 2018). Although the functional significance of this observation is yet to be determined, it is tempting to speculate that there may be a crosstalk between Rho5-mediated cell death pathway and glucose signaling.…”

Section: Resultsmentioning

confidence: 99%

Genome-Wide Studies of Rho5-Interacting Proteins That Are Involved in Oxidant-Induced Cell Death in Budding Yeast

Singh

Lee

Entezari

et al. 2019

G3 Genes|Genomes|Genetics

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Rho GTPases play critical roles in cell proliferation and cell death in many species. As in animal cells, cells of the budding yeast Saccharomyces cerevisiae undergo regulated cell death under various physiological conditions and upon exposure to external stress. The Rho5 GTPase is necessary for oxidant-induced cell death, and cells expressing a constitutively active GTP-locked Rho5 are hypersensitive to oxidants. Yet how Rho5 regulates yeast cell death has been poorly understood. To identify genes that are involved in the Rho5 -mediated cell death program, we performed two complementary genome-wide screens: one screen for oxidant-resistant deletion mutants and another screen for Rho5 -associated proteins. Functional enrichment and interaction network analysis revealed enrichment for genes in pathways related to metabolism, transport, and plasma membrane organization. In particular, we find that ATG21 , which is known to be involved in the CVT (Cytoplasm-to-Vacuole Targeting) pathway and mitophagy, is necessary for cell death induced by oxidants. Cells lacking Atg21 exhibit little cell death upon exposure to oxidants even when the GTP-locked Rho5 is expressed. Moreover, Atg21 interacts with Rho5 preferentially in its GTP-bound state, suggesting that Atg21 is a downstream target of Rho5 in oxidant-induced cell death. Given the high degree of conservation of Rho GTPases and autophagy from yeast to human, this study may provide insight into regulated cell death in eukaryotes in general.

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“…The Mtl1 mechanosensor appears to be important in this respect, and it has been shown that Mtl1 activates the CWI pathway in response to glucose starvation [178]. Recent data indicate that Rho5, which is down-stream of the mechanosensors, might be involved in the response to glucose starvation [179], which gives further support for the involvement of the mechanosensors in nutrient sensing. Further mechanistic insights into this nutrient-sensing hypothesis comes from the fact that Wsc1, Wsc2, Wsc3, and Mtl1 have all been identified as inhibitors of the RAS2-cAMP pathway [145, 180].…”

Section: The Yeast Cell Wall and Mechanosensors As Mediators Of Variomentioning

confidence: 98%

Integrins in disguise – mechanosensors in Saccharomyces cerevisiae as functional integrin analogues

Elhasi¹,

Blomberg²

2019

Microb Cell

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The ability to sense external mechanical stimuli is vital for all organisms. Integrins are transmembrane receptors that mediate bidirectional signalling between the extracellular matrix (ECM) and the cytoskeleton in animals. Thus, integrins can sense changes in ECM mechanics and can translate these into internal biochemical responses through different signalling pathways. In the model yeast species Saccharomyces cerevisiae there are no proteins with sequence similarity to mammalian integrins. However, we here emphasise that the WSC-type (Wsc1, Wsc2, and Wsc3) and the MID-type (Mid2 and Mtl1) mechanosensors in yeast act as partial functional integrin analogues. Various environmental cues recognised by these mechanosensors are transmitted by a conserved signal transduction cascade commonly referred to as the PKC1-SLT1 cell wall integrity (CWI) pathway. We exemplify the WSC- and MID-type mechanosensors functional analogy to integrins with a number of studies where they resemble the integrins in terms of both mechanistic and molecular features as well as in the overall phenotypic consequences of their activity. In addition, many important components in integrin-dependent signalling in humans are conserved in yeast; for example, Sla1 and Sla2 are homologous to different parts of human talin, and we propose that they together might be functionally similar to talin. We also propose that the yeast cell wall is a prominent cellular feature involved in sensing a number of external factors and subsequently activating different signalling pathways. In a hypothetical model, we propose that nutrient limitations modulate cell wall elasticity, which is sensed by the mechanosensors and results in filamentous growth. We believe that mechanosensing is a somewhat neglected aspect of yeast biology, and we argue that the physiological and molecular consequences of signal transduction initiated at the cell wall deserve more attention.

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The Small Yeast GTPase Rho5 and Its Dimeric GEF Dck1/Lmo1 Respond to Glucose Starvation

Cited by 16 publications

References 58 publications

Analysis of Functional Domains in Rho5, the Yeast Homolog of Human Rac1 GTPase, in Oxidative Stress Response

Analysis of Functional Domains in Rho5, the Yeast Homolog of Human Rac1 GTPase, in Oxidative Stress Response

Genome-Wide Studies of Rho5-Interacting Proteins That Are Involved in Oxidant-Induced Cell Death in Budding Yeast

Integrins in disguise – mechanosensors in Saccharomyces cerevisiae as functional integrin analogues

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