Hyperactive <scp>TORC</scp>1 sensitizes yeast cells to endoplasmic reticulum stress by compromising cell wall integrity

Ahmed, Khadija; Carter, David E.; Lajoie, Patrick

doi:10.1002/1873-3468.13463

Cited by 15 publications

(9 citation statements)

References 110 publications

(120 reference statements)

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“…Opi1 has been shown to be a substrate for PKA phosphorylation, which enhances its activity as a repressor of INO1 [73]. Moreover, it was previously demonstrated that a hyperactive variant of the TORC1 kinase complex (TOR1 L2134M allele) reduced the expression of INO1 [74]. Based on the results reported in this manuscript, we posit that weakened electrostatic interaction of Opi1 with PA promoted by decreased cytosolic pH is sufficient to favor Opi1 repressor activity and reduce INO1 transcription (Figure 6A), and confer an inositol auxotrophy phenotype (Figure 5E), thus leading to LD dyshomeostasis (Figure 6B).…”

Section: Uncoupling Opi1 Activity From Pa Binding Is Sufficient To Induce Inositol-dependent Phenotypes and Ld Generationmentioning

confidence: 99%

Target of Rapamycin Complex 1 (TORC1), Protein Kinase A (PKA) and Cytosolic pH Regulate a Transcriptional Circuit for Lipid Droplet Formation

Teixeira

Martins

Prinz

et al. 2021

IJMS

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Lipid droplets (LDs) are ubiquitous organelles that fulfill essential roles in response to metabolic cues. The identification of several neutral lipid synthesizing and regulatory protein complexes have propelled significant advance on the mechanisms of LD biogenesis in the endoplasmic reticulum (ER). However, our understanding of signaling networks, especially transcriptional mechanisms, regulating membrane biogenesis is very limited. Here, we show that the nutrient-sensing Target of Rapamycin Complex 1 (TORC1) regulates LD formation at a transcriptional level, by targeting DGA1 expression, in a Sit4-, Mks1-, and Sfp1-dependent manner. We show that cytosolic pH (pHc), co-regulated by the plasma membrane H+-ATPase Pma1 and the vacuolar ATPase (V-ATPase), acts as a second messenger, upstream of protein kinase A (PKA), to adjust the localization and activity of the major transcription factor repressor Opi1, which in turn controls the metabolic switch between phospholipid metabolism and lipid storage. Together, this work delineates hitherto unknown molecular mechanisms that couple nutrient availability and pHc to LD formation through a transcriptional circuit regulated by major signaling transduction pathways.

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Section: Uncoupling Opi1 Activity From Pa Binding Is Sufficient To Induce Inositol-dependent Phenotypes and Ld Generationmentioning

confidence: 99%

Target of Rapamycin Complex 1 (TORC1), Protein Kinase A (PKA) and Cytosolic pH Regulate a Transcriptional Circuit for Lipid Droplet Formation

Teixeira

Martins

Prinz

et al. 2021

IJMS

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“…Moreover, the relationship among ER stress, cell wall integrity and various signaling cascades has been reported in different fungi. These signaling cascades are exemplified by the target of rapamycin (TOR) and calcium/calcineurin pathways [74][75][76]. In this study, we indicated that the Mkc1 MAPK pathway is involved in the Sfp1-regulated cell response to LL-37 (Figure 2C).…”

Section: Discussionmentioning

confidence: 60%

Candida albicans Sfp1 Is Involved in the Cell Wall and Endoplasmic Reticulum Stress Responses Induced by Human Antimicrobial Peptide LL-37

Hsu

Liao

Chang

et al. 2021

IJMS

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Candida albicans is a commensal fungus of humans but can cause infections, particularly in immunocompromised individuals, ranging from superficial to life-threatening systemic infections. The cell wall is the outermost layer of C. albicans that interacts with the host environment. Moreover, antimicrobial peptides (AMPs) are important components in innate immunity and play crucial roles in host defense. Our previous studies showed that the human AMP LL-37 binds to the cell wall of C. albicans, alters the cell wall integrity (CWI) and affects cell adhesion of this pathogen. In this study, we aimed to further investigate the molecular mechanisms underlying the C. albicans response to LL-37. We found that LL-37 causes cell wall stress, activates unfolded protein response (UPR) signaling related to the endoplasmic reticulum (ER), induces ER-derived reactive oxygen species and affects protein secretion. Interestingly, the deletion of the SFP1 gene encoding a transcription factor reduced C. albicans susceptibility to LL-37, which is cell wall-associated. Moreover, in the presence of LL-37, deletion of SFP1 attenuated the UPR pathway, upregulated oxidative stress responsive (OSR) genes and affected bovine serum albumin (BSA) degradation by secreted proteases. Therefore, these findings suggested that Sfp1 positively regulates cell wall integrity and ER homeostasis upon treatment with LL-37 and shed light on pathogen-host interactions.

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“…In F. oxysporum , the cell wall is mainly composed of glucans, chitin, and glycoproteins (Schoffelmeer et al, 1999) and its integrity is essential for development and virulence (Fernandes et al, 2021; Martin‐Udiroz et al, 2004; Nunez‐Rodriguez et al, 2020). Interestingly, S. cerevisiae cells expressing a hyperactive TOR1 allele were impaired in β‐1‐3‐glucan synthesis and exhibited increased sensitivity to cell wall‐perturbing compounds (Ahmed et al, 2019). Furthermore, in F. graminearum loss of Sit4, a phosphatase that is inactivated by TORC1, caused increased sensitivity to cell wall‐damaging agents and to high temperature stress (Yu et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Constitutive activation of TORC1 signalling attenuates virulence in the cross‐kingdom fungal pathogen Fusarium oxysporum

Navarro-Velasco

Pietro

López‐Berges

2023

Molecular Plant Pathology

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The filamentous fungus Fusarium oxysporum causes vascular wilt disease in a wide range of plant species and opportunistic infections in humans. Previous work suggested that invasive growth in this pathogen is controlled by environmental cues such as pH and nutrient status. Here we investigated the role of Target Of Rapamycin Complex 1 (TORC1), a global regulator of eukaryotic cell growth and development. Inactivation of the negative regulator Tuberous Sclerosis Complex 2 (Tsc2), but not constitutive activation of the positive regulator Gtr1, in F. oxysporum resulted in inappropriate activation of TORC1 signalling under nutrient‐limiting conditions. The tsc2Δ mutants showed reduced colony growth on minimal medium with different nitrogen sources and increased sensitivity to cell wall or high temperature stress. Furthermore, these mutants were impaired in invasive hyphal growth across cellophane membranes and exhibited a marked decrease in virulence, both on tomato plants and on the invertebrate animal host Galleria mellonella. Importantly, invasive hyphal growth in tsc2Δ strains was rescued by rapamycin‐mediated inhibition of TORC1. Collectively, these results reveal a key role of TORC1 signalling in the development and pathogenicity of F. oxysporum and suggest new potential targets for controlling fungal infections.

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Hyperactive TORC1 sensitizes yeast cells to endoplasmic reticulum stress by compromising cell wall integrity

Cited by 15 publications

References 110 publications

Target of Rapamycin Complex 1 (TORC1), Protein Kinase A (PKA) and Cytosolic pH Regulate a Transcriptional Circuit for Lipid Droplet Formation

Target of Rapamycin Complex 1 (TORC1), Protein Kinase A (PKA) and Cytosolic pH Regulate a Transcriptional Circuit for Lipid Droplet Formation

Candida albicans Sfp1 Is Involved in the Cell Wall and Endoplasmic Reticulum Stress Responses Induced by Human Antimicrobial Peptide LL-37

Constitutive activation of TORC1 signalling attenuates virulence in the cross‐kingdom fungal pathogen Fusarium oxysporum

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