TORC2 and eisosomes are spatially interdependent, requiring optimal level of phosphatidylinositol 4, 5-bisphosphate for their integrity

Bartlett, Katelyn; Gadila, Shiva Kumar Goud; Tenay, Brandon; McDermott, Hyoeun; Alcox, Brett; Kim, Dong Kyu

doi:10.1007/s12038-015-9526-4

Cited by 14 publications

(16 citation statements)

References 54 publications

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“…Moreover, it had been suggested that these two compartments are discrete (Berchtold and Walther 2009). However, as we found and document here, a substantial fraction of Avo2 is readily found in association with the diagnostic eisosome marker Pil1, in agreement with the observations of at least one other group (Bartlett et al 2015). Furthermore, there is convincing evidence that the Avo2-interacting proteins and eisosome components Slm1 and Slm2 are required for TORC2-mediated phosphorylation of Ypk1 (Berchtold et al 2012;Niles et al 2012).…”

Section: Discussionsupporting

confidence: 92%

“…Initially, it was reported that all of the components of TORC2, including Avo2, reside in a PM microdomain dubbed the "MCT" that is distinct from eisosomes (Berchtold and Walther 2009). However, subsequent work demonstrated that Avo2 partitions between TORC2 and eisosomes (Bartlett et al 2015). For these reasons, and having established that MAPK phosphorylation does not affect Avo2 stability ( Figs.…”

Section: Mapk Phosphorylation Of Avo2 Alters Its Subcellular Localizamentioning

confidence: 98%

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Phosphorylation by the stress-activated MAPK Slt2 down-regulates the yeast TOR complex 2

Leskoske

Roelants

Emmerstorfer-Augustin

et al. 2018

Genes Dev.

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Saccharomyces cerevisiae target of rapamycin (TOR) complex 2 (TORC2) is an essential regulator of plasma membrane lipid and protein homeostasis. How TORC2 activity is modulated in response to changes in the status of the cell envelope is unclear. Here we document that TORC2 subunit Avo2 is a direct target of Slt2, the mitogenactivated protein kinase (MAPK) of the cell wall integrity pathway. Activation of Slt2 by overexpression of a constitutively active allele of an upstream Slt2 activator (Pkc1) or by auxin-induced degradation of a negative Slt2 regulator (Sln1) caused hyperphosphorylation of Avo2 at its MAPK phosphoacceptor sites in a Slt2-dependent manner and diminished TORC2-mediated phosphorylation of its major downstream effector, protein kinase Ypk1. Deletion of Avo2 or expression of a phosphomimetic Avo2 allele rendered cells sensitive to two stresses (myriocin treatment and elevated exogenous acetic acid) that the cell requires Ypk1 activation by TORC2 to survive. Thus, Avo2 is necessary for optimal TORC2 activity, and Slt2-mediated phosphorylation of Avo2 down-regulates TORC2 signaling. Compared with wild-type Avo2, phosphomimetic Avo2 shows significant displacement from the plasma membrane, suggesting that Slt2 inhibits TORC2 by promoting Avo2 dissociation. Our findings are the first demonstration that TORC2 function is regulated by MAPK-mediated phosphorylation.

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Section: Discussionsupporting

confidence: 92%

Section: Mapk Phosphorylation Of Avo2 Alters Its Subcellular Localizamentioning

confidence: 98%

Phosphorylation by the stress-activated MAPK Slt2 down-regulates the yeast TOR complex 2

Leskoske

Roelants

Emmerstorfer-Augustin

et al. 2018

Genes Dev.

View full text Add to dashboard Cite

show abstract

“…Thus we investigated whether overproduction of elements of the TORC2 pathway (the Pkh2 kinase; TORC2 components Avo1, Avo2, Avo3 and Tor2; downstream AGC kinases Pkc1, Sch9 and Ypk1; and the Slm1 adaptor) led to effects similar to those caused by Akt. We also overproduced TORC2-signaling targets, like ceramide synthases Lac1 and Lag1 27 , and MCC/eisosome components Lsp1, Pil1 and Sur7 12 , because MCC/eisosomes are also related to PtdIns4,5P 2 regulation 11 , 48 . As shown in Table S1 and Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In the latest years, accumulated evidence indicates that the PM is organized in mosaic-like microdomains, the most prominent being the Membrane Compartment containing Pma1 (MCP), the Membrane Compartment containing Can1 (MCC; coincident with a furrow-like structure named eisosome), and the Membrane Compartment containing Tor2 (MCT) 7 , 8 , but there are probably less conspicuous PM microdomains 9 . MCP compartments have been reported to be active sites of endo- and exocytosis 10 , whereas the MCC and MCT are involved in PtdIns4,5P 2 homeostasis 11 . The invaginated PM furrows of MCCs are characteristically marked by BAR domain-containing proteins Pil1 and Lsp1 12 , 13 .…”

Section: Introductionmentioning

confidence: 99%

Heterologous mammalian Akt disrupts plasma membrane homeostasis by taking over TORC2 signaling in Saccharomyces cerevisiae

Rodríguez-Escudero

Fernández-Acero

Cid

et al. 2018

Sci Rep

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The Akt protein kinase is the main transducer of phosphatidylinositol-3,4,5-trisphosphate (PtdIns3,4,5P3) signaling in higher eukaryotes, controlling cell growth, motility, proliferation and survival. By co-expression of mammalian class I phosphatidylinositol 3-kinase (PI3K) and Akt in the Saccharomyces cerevisiae heterologous model, we previously described an inhibitory effect on yeast growth that relied on Akt kinase activity. Here we report that PI3K-Akt expression in yeast triggers the formation of large plasma membrane (PM) invaginations that were marked by actin patches, enriched in PtdIns4,5P2 and associated to abnormal intracellular cell wall deposits. These effects of Akt were mimicked by overproduction of the PtdIns4,5P2 effector Slm1, an adaptor of the Ypk1 and Ypk2 kinases in the TORC2 pathway. Although Slm1 was phosphorylated in vivo by Akt, TORC2-dependent Ypk1 activation did not occur. However, PI3K-activated Akt suppressed the lethality derived from inactivation of either TORC2 or Ypk protein kinases. Thus, heterologous co-expression of PI3K and Akt in yeast short-circuits PtdIns4,5P2- and TORC2-signaling at the level of the Slm-Ypk complex, overriding some of its functions. Our results underscore the importance of phosphoinositide-dependent kinases as key actors in the homeostasis and dynamics of the PM.

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“…ATG1 is a downstream substrate of TOR, but evidence from Drosophila suggests ATG1 can also be an upstream regulator of TOR [ 48 ]. MDG1/YNL173C is also a component of the yeast eisosome [ 49 ], a membrane microdomain that interacts with TORC2 [ 50 ]. Although Abl1, according to PSORTII, is not predicted to be membrane localized, these potential links between MDG1/YNL173C and TOR in yeast might give tantalizing hints about how Abl1, and thus glucose, regulates TOR in M .…”

Section: Discussionmentioning

confidence: 99%

Glucose-ABL1-TOR Signaling Modulates Cell Cycle Tuning to Control Terminal Appressorial Cell Differentiation

2017

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The conserved target of rapamycin (TOR) pathway integrates growth and development with available nutrients, but how cellular glucose controls TOR function and signaling is poorly understood. Here, we provide functional evidence from the devastating rice blast fungus Magnaporthe oryzae that glucose can mediate TOR activity via the product of a novel carbon-responsive gene, ABL1, in order to tune cell cycle progression during infection-related development. Under nutrient-free conditions, wild type (WT) M. oryzae strains form terminal plant-infecting cells (appressoria) at the tips of germ tubes emerging from three-celled spores (conidia). WT appressorial development is accompanied by one round of mitosis followed by autophagic cell death of the conidium. In contrast, Δabl1 mutant strains undergo multiple rounds of accelerated mitosis in elongated germ tubes, produce few appressoria, and are abolished for autophagy. Treating WT spores with glucose or 2-deoxyglucose phenocopied Δabl1. Inactivating TOR in Δabl1 mutants or glucose-treated WT strains restored appressorium formation by promoting mitotic arrest at G1/G0 via an appressorium- and autophagy-inducing cell cycle delay at G2/M. Collectively, this work uncovers a novel glucose-ABL1-TOR signaling axis and shows it engages two metabolic checkpoints in order to modulate cell cycle tuning and mediate terminal appressorial cell differentiation. We thus provide new molecular insights into TOR regulation and cell development in response to glucose.

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TORC2 and eisosomes are spatially interdependent, requiring optimal level of phosphatidylinositol 4, 5-bisphosphate for their integrity

Cited by 14 publications

References 54 publications

Phosphorylation by the stress-activated MAPK Slt2 down-regulates the yeast TOR complex 2

Phosphorylation by the stress-activated MAPK Slt2 down-regulates the yeast TOR complex 2

Heterologous mammalian Akt disrupts plasma membrane homeostasis by taking over TORC2 signaling in Saccharomyces cerevisiae

Glucose-ABL1-TOR Signaling Modulates Cell Cycle Tuning to Control Terminal Appressorial Cell Differentiation

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