Ferroptosis-Protective Membrane Domains in Quiescence

Megarioti, Amalia H; Αθανασόπουλος, Αλέξανδρος; Koulouris, Dimitrios; Esch, Bianca M.; Makridakis, Manousos; Lygirou, Vasiliki; Samiotaki, Martina; Zoidakis, Jérôme; Sophianopoulou, Vicky; André, Brunó; Fröhlich, Florian; Gournas, Christos

doi:10.2139/ssrn.4431131

Cited by 2 publications

(2 citation statements)

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“…Organisation of the yeast PM is complex, with various surface localisation patterns known for both integral membrane proteins and surface associated factors ( Spira et al, 2012 ). Since the discovery of eisosome subdomains, progress has been made in understanding the formation and biological function of these structures, particularly in response to cellular stress ( Babst, 2019 ; Megarioti et al, 2023 preprint; Moseley, 2018 ). The discovery that Pil1 and Lsp1, and their phosphorylation by the Pkh family kinases, are required for proper eisosome biogenesis ( Walther et al, 2007 , 2006 ) suggests that post-translational modification of core components could regulate the eisosome environment.…”

Section: Discussionmentioning

confidence: 99%

“…However, as the changes we observe in both Pil1 dephosphorylation and transporter retention are very rapid, we assume these effects are not mediated at the transcriptional level. Other eisosome based regulation is known to span much longer periods of starvation ( Gournas et al, 2018b ; Megarioti et al, 2023 preprint) and likely to have transcriptionally based control. In further support of this being a novel and distinct role for Glc7, the regulatory subunit Reg1, which is required for many transcriptional related Glc7 activities ( Alms et al, 1999 ; Cui et al, 2004 ; Dombek et al, 1999 ), or its paralogue Reg2 ( Frederick and Tatchell, 1996 ), showed no increase in phosphorylated Pil1 species upon deletion ( Fig.…”

Section: Discussionmentioning

confidence: 99%

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The phosphatase Glc7 controls the eisosomal response to starvation via post-translational modification of Pil1

Paine

Laidlaw

Evans

et al. 2023

Journal of Cell Science

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The yeast plasma membrane (PM) is organised into specific subdomains that regulate surface membrane proteins. Surface transporters actively uptake nutrients in particular regions of the PM where they are also susceptible to substrate induced endocytosis. However, transporters also diffuse into distinct subdomains termed eisosomes, where they are protected from endocytosis. Although most nutrient transporter populations are downregulated in the vacuole following glucose starvation, a small pool is retained in eisosomes to provide efficient recovery from starvation. We find the core eisosome subunit Pil1, a Bin, Amphiphysin and Rvs (BAR) domain protein required for eisosome biogenesis, is phosphorylated primarily by the kinase Pkh2. In response to acute glucose starvation, Pil1 is rapidly dephosphorylated. Enzyme localisation and activity screens implicate the phosphatase Glc7 is the primary enzyme responsible for Pil1 dephosphorylation. Both depletion of GLC7 and phospho-ablative or phospho-mimetic mutations of Pil1 correlate with Pil1 phosphorylation status, failure to properly retain transporters in eisosomes, and results in defective starvation recovery. We propose precise posttranslational control of Pil1 modulates nutrient transporter retention within eisosomes depending on extracellular nutrient levels, to maximise recovery following starvation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The phosphatase Glc7 controls the eisosomal response to starvation via post-translational modification of Pil1

Paine

Laidlaw

Evans

et al. 2023

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

The phosphatase Glc7 controls eisosomal response to starvation via posttranslational modification of Pil1

Paine

Evans

Laidlaw

et al. 2022

Preprint

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The yeast plasma membrane (PM) is organised into specific subdomains that can regulate the activity of surface membrane proteins localised within them. Nutrient transporters actively uptake substrates in particular regions of the PM where they are also susceptible to the endocytic machinery for substrate induced degradation. However, transporters also diffuse into distinct subdomains termed eisosomes, where they are inactive for substrate uptake and are protected from endocytosis. Although most nutrient transporter populations are sorted to the vacuole for degradation during glucose starvation, a small pool are retained in eisosomes. Sequestering this small pool of transporters during nutrient stress is essential for efficient recovery from starvation following a return to replete conditions. However, the mechanisms controlling this process at a biochemical level are poorly defined. We find the core eisosome subunit Pil1, a Bin, Amphiphysin and Rvs. (BAR) domain protein involved in membrane dynamics required for eisosome biogenesis, is primarily phosphorylated by Pkh2 but that Pil1 dephosphorylation occurs during acute glucose starvation. We screened for enzyme localisation and activity to implicate the essential phosphatase Glc7 as the primary enzyme responsible for Pil1 dephosphorylation. Manipulation of GLC7 expression correlates with Pil1 hypo/hyper phosphorylation. Furthermore, glc7 mutants and Pil1-phosphomutants are defective in recovering from glucose starvation. We propose precise posttranslational control of Pil1 modulates nutrient transporter retention within eisosomes depending on cellular nutritional status, to maximise recovery from starvation.

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Ferroptosis-Protective Membrane Domains in Quiescence

Cited by 2 publications

References 88 publications

The phosphatase Glc7 controls the eisosomal response to starvation via post-translational modification of Pil1

The phosphatase Glc7 controls the eisosomal response to starvation via post-translational modification of Pil1

The phosphatase Glc7 controls eisosomal response to starvation via posttranslational modification of Pil1

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