Redox signals at theER–mitochondria interface control melanoma progression

The EMBO Journal, Год журнала: 2019, Номер 38(15)

Опубликована: Июль 15, 2019

Reactive oxygen species (ROS) are emerging as important regulators of cancer growth and metastatic spread. However, how cells integrate redox signals to affect progression is not fully understood. Mitochondria cellular hubs, which highly regulated by interactions with neighboring organelles. Here, we investigated ROS at the endoplasmic reticulum (ER)-mitochondria interface generated translated melanoma outcome. We show that TMX1 TMX3 oxidoreductases, promote ER-mitochondria communication, upregulated in patient samples. TMX knockdown altered mitochondrial organization, enhanced bioenergetics, elevated mitochondrial- NOX4-derived ROS. The TMX-knockdown-induced oxidative stress suppressed proliferation, migration, xenograft tumor inhibiting NFAT1. Furthermore, identified NFAT1-positive NFAT1-negative subgroups, wherein NFAT1 expression correlates stage potential. Integrative bioinformatics revealed genes coding for redox-related proteins under control indicated TMX1, TMX3, associated poor disease Our study unravels a novel redox-controlled ER-mitochondria-NFAT1 signaling loop regulates pathobiology provides biomarkers indicative aggressive disease.

Язык: Английский

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The STIM-Orai coupling interface and gating of the Orai1 channel

Cell Calcium, Год журнала: 2017, Номер 63, С. 8 - 13

Опубликована: Янв. 8, 2017

Язык: Английский

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Cross-linking of Orai1 channels by STIM proteins

Proceedings of the National Academy of Sciences, Год журнала: 2018, Номер 115(15)

Опубликована: Март 26, 2018

Significance The work presents a unique understanding of the organization and function two ubiquitously expressed proteins, central in generating calcium signals all cell types. These are intracellular sensing “STIM” highly selective surface “Orai” channels. We reveal that STIM proteins can cross-link Orai channels, resulting reorganized microenvironment within membrane junctions which they function, with important consequences generation oscillatory signals. Interestingly, we show variant protein widely cells functions to prevent STIM–Orai cross-linking clustering This provides modulation signal serve protect from overstimulation signaling machinery.

Язык: Английский

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Intracellular tortuosity underlies slow cAMP diffusion in adult ventricular myocytes

Cardiovascular Research, Год журнала: 2016, Номер 110(3), С. 395 - 407

Опубликована: Апрель 18, 2016

3′,5′-Cyclic adenosine monophosphate (cAMP) signals in the heart are often confined to concentration microdomains shaped by cAMP diffusion and enzymatic degradation. While importance of phosphodiesterases (degradative enzymes) sculpting is well established cardiomyocytes, less known about diffusivity (DcAMP) factors affecting it. Many earlier studies have reported fast diffusivity, which argues against sharply defined microdomains. [cAMP] dynamics cytoplasm adult rat ventricular myocytes were imaged using a fourth generation genetically encoded FRET-based sensor. The [cAMP]-response addition removal isoproterenol (β-adrenoceptor agonist) quantified rates synthesis To obtain read out DcAMP, stable gradient was generated microfluidic device delivered agonist one half myocyte only. After accounting for phosphodiesterase activity, DcAMP calculated be 32 µm2/s; an order magnitude lower than water. Diffusivity independent amount produced. Saturating cAMP-binding sites with analogue 6-Bnz-cAMP did not accelerate arguing role buffering restricting mobility. diffused at comparable rate chemically unrelated but similar sized molecules, common physical cause restricted diffusivity. Lower mitochondrial density neonatal cardiac allowed faster diffusion, demonstrating mitochondria as barriers In myocytes, tortuosity due barriers, notably mitochondria, restricts levels that more compatible microdomain signalling.

Язык: Английский

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A calcium-accumulating region, CAR, in the channel Orai1 enhances Ca ²⁺ permeation and SOCE-induced gene transcription

Science Signaling, Год журнала: 2015, Номер 8(408)

Опубликована: Дек. 22, 2015

The Ca(2+) release-activated channel mediates influx in a plethora of cell types, thereby controlling diverse cellular functions. complex is composed stromal interaction molecule 1 (STIM1), an endoplasmic reticulum Ca(2+)-sensing protein, and Orai1, plasma membrane channel. Channels STIM1 Orai1 mediate even at low extracellular concentrations. We investigated whether the activity adapted to different environmental used homology modeling molecular dynamics simulations predict presence Ca(2+)-accumulating region (CAR) pore entrance Orai1. Furthermore, proteins with mutations CAR, along live-cell experiments, or electrophysiological recordings transient, electrostatic loop3 interacting loop1 (the site CAR) determined that CAR enhanced permeation most efficiently external Consistent these results, cells expressing mutants exhibited impaired gene expression stimulated by Ca(2+)-activated transcription factor nuclear activated T (NFAT). propose architecture close proximity selectivity filter, which enables Ca(2+)-selective ion permeation, enhances local concentration maintain Ca(2+)-dependent regulation environments relatively Ca(2+)concentrations.

Язык: Английский

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