The mitogen‐activated protein kinase Slt2 modulates arsenite transport through the aquaglyceroporin Fps1

Ahmadpour, Doryaneh; Maciaszczyk-Dziubińska, Ewa; Babazadeh, Roja; Dahal, Sita; Migocka, Magdalena; Andersson, Mikael; Wysocki, Robert; Tamás, Markus J.; Hohmann, Stefan

doi:10.1002/1873-3468.12390

Cited by 22 publications

(24 citation statements)

References 43 publications

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“…S2 " type="url"/> ; ). A set of hits with reduced aggregation levels were related to As(III) import, including Fps1, the aquaglyceroporin that mediates As(III) entry into cells ( Wysocki et al, 2001 ), and positive regulators of Fps1 [Rgc1, Rgc2 (also known as Ask10) ( Beese et al, 2009 ) and Slt2 ( Ahmadpour et al, 2016 )] ( ).…”

Section: Resultsmentioning

confidence: 99%

Genome-wide imaging screen uncovers molecular determinants of arsenite-induced protein aggregation and toxicity

Andersson

Romero

Rodrigues

et al. 2021

Journal of Cell Science

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The toxic metalloid arsenic causes widespread misfolding and aggregation of cellular proteins. How these protein aggregates are formed in vivo, the mechanisms by which they affect cells, and how cells prevent their accumulation is not fully understood. To find components involved in these processes, we performed a genome-wide imaging screen and identified yeast deletion mutants with either enhanced or reduced protein aggregation levels during arsenite exposure. We show that many of the identified factors are crucial to safeguard protein homeostasis (proteostasis) and to protect cells against arsenite toxicity. The hits were enriched for various functions including protein biosynthesis and transcription, and dedicated follow-up experiments highlight the importance of accurate transcriptional and translational control for mitigating protein aggregation and toxicity during arsenite stress. Some of the hits are associated with pathological conditions, suggesting that arsenite-induced protein aggregation may affect disease processes. The broad network of cellular systems that impinge on proteostasis during arsenic stress identified in this current study provides a valuable resource and a framework for further elucidation of the mechanistic details of metalloid toxicity and pathogenesis.

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Section: Resultsmentioning

confidence: 99%

Genome-wide imaging screen uncovers molecular determinants of arsenite-induced protein aggregation and toxicity

Andersson

Romero

Rodrigues

et al. 2021

Journal of Cell Science

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“…For example, the Fps1 channels, which export glycerol through the plasma membrane, are not only controlled by Hog1, but also have additional regulation (Luyten et al, 1995; Ahmadpour et al, 2016). Their fast closure gives an initial boost of glycerol (Petelenz-Kurdziel et al, 2013), which is important in all three mutants because the glycerol produced from nuclear Hog1 accumulates relatively slowly, over the time-scale of the integrator.…”

Section: Resultsmentioning

confidence: 99%

Distributing tasks via multiple input pathways increases cellular survival in stress

Granados

Crane

Montaño-Gutierrez

et al. 2017

eLife

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Improving in one aspect of a task can undermine performance in another, but how such opposing demands play out in single cells and impact on fitness is mostly unknown. Here we study budding yeast in dynamic environments of hyperosmotic stress and show how the corresponding signalling network increases cellular survival both by assigning the requirements of high response speed and high response accuracy to two separate input pathways and by having these pathways interact to converge on Hog1, a p38 MAP kinase. Cells with only the less accurate, reflex-like pathway are fitter in sudden stress, whereas cells with only the slow, more accurate pathway are fitter in increasing but fluctuating stress. Our results demonstrate that cellular signalling is vulnerable to trade-offs in performance, but that these trade-offs can be mitigated by assigning the opposing tasks to different signalling subnetworks. Such division of labour could function broadly within cellular signal transduction.DOI: http://dx.doi.org/10.7554/eLife.21415.001

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“…With regard to signaling, As(III) stimulates the mammalian stress-activated MAPK (SAPK) p38 ( Elbirt et al , 1998 ; Verma et al , 2002 ) and both SAPKs of yeast—Hog1 of the high osmolarity glycerol (HOG) pathway ( Sotelo and Rodríguez-Gabriel, 2006 ; Thorsen et al , 2006 ) and Mpk1 (Slt2) of the cell wall integrity pathway ( Ahmadpour et al , 2016 ). As(V) also activates Mpk1 ( Matia-Gonzalez and Rodriguez-Gabriel, 2011 ), but has not been shown to activate Hog1.…”

Section: Introductionmentioning

confidence: 99%

Intracellular mechanism by which arsenite activates the yeast stress MAPK Hog1

Lee

Levin

2018

MBoC

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Stress-activated MAPKs (SAPKs) respond to a wide variety of stressors. In most cases, the pathways through which specific stress signals are transmitted to the SAPKs are not known. In this study, we delineate the intracellular signaling pathway by which the trivalent toxic metalloid arsenite [As(III)] activates the yeast SAPK Hog1. We demonstrate that, to activate Hog1, As(III) must enter the cell through the glycerol channel Fps1 and must be metabolized to methyl arsenite [MAs(III)] by the dimeric methyltransferase Mtq2:Trm112. We found that Mtq2:Trm1 displays SAM-dependent methyltransferase activity toward both As(III) and MAs(III). Additionally, we present genetic and biochemical evidence that MAs(III), but not As(III), is a potent inhibitor of the protein tyrosine phosphatases (Ptp2 and Ptp3) that normally maintain Hog1 in an inactive state. Inhibition of Ptp2 and Ptp3 by MAs(III) results in elevated Hog1 phosphorylation without activation of the protein kinases that act upstream of the SAPK and raises the possibility that other Hog1-activating stressors act intracellularly at different points along the canonical Hog1 activation pathway. Finally, we show that arsenate [As(V)], a pentavalent form of arsenic, also activates Hog1, but through a pathway that is distinct from that of As(III) and involves activation of the Hog1 MEK Pbs2.

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The mitogen‐activated protein kinase Slt2 modulates arsenite transport through the aquaglyceroporin Fps1

Cited by 22 publications

References 43 publications

Genome-wide imaging screen uncovers molecular determinants of arsenite-induced protein aggregation and toxicity

Genome-wide imaging screen uncovers molecular determinants of arsenite-induced protein aggregation and toxicity

Distributing tasks via multiple input pathways increases cellular survival in stress

Intracellular mechanism by which arsenite activates the yeast stress MAPK Hog1

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