Getting the Message? Native Reactive Electrophiles Pass Two Out of Three Thresholds to be Bona Fide Signaling Mediators

Poganik, Jesse R.; Long, Marcus J. C.; Aye, Yimon

doi:10.1002/bies.201700240

Cited by 19 publications

(38 citation statements)

References 113 publications

(264 reference statements)

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“…Reactive aldehyde species (RAS), such as AcH, are becoming increasingly appreciated for their roles in initiating signaling responses (Poganik et al., ; Raza and John, ). Adducts formed from covalent modifications with the electrophilic groups may not only act as toxic stimuli but also serve as relevant posttranslational modifications for proteins to affect downstream signaling pathways (Poganik et al., ). What effects these changes have on stem cell biology are still largely unknown at a mechanistic level.…”

Section: Discussionmentioning

confidence: 99%

Different Effects of Knockouts in ALDH2 and ACSS2 on Embryonic Stem Cell Differentiation

Serio

Gross

et al. 2019

Alcoholism Clin & Exp Res

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Background: Ethanol (EtOH) is a teratogen that causes severe birth defects, but the mechanisms by which EtOH affects stem cell differentiation are unclear. Our goal here is to examine the effects of EtOH and its metabolites, acetaldehyde (AcH) and acetate, on embryonic stem cell (ESC) differentiation.Methods: We designed ESC lines in which aldehyde dehydrogenase (ALDH2, NCBI#11669) and acyl-CoA synthetase short-chain family member 2 (ACSS2, NCBI#60525) were knocked out by CRISPR-Cas9 technology. We selected these genes because of their key roles in EtOH oxidation in order to dissect the effects of EtOH metabolism on differentiation.Results: By using kinetic assays, we confirmed that AcH is primarily oxidized by ALDH2 rather than ALDH1A2. We found increases in mRNAs of differentiation-associated genes (Hoxa1, Cyp26a1, and RARb2) upon EtOH treatment of WT and Acss2 À/À ESCs, but not Aldh2 À/À ESCs. The absence of ALDH2 reduced mRNAs of some pluripotency factors (Nanog, Sox2, and Klf4). Treatment of WT ESCs with AcH or 4-hydroxynonenal (4-HNE), another substrate of ALDH2, increased differentiation-associated transcripts compared to levels in untreated cells. mRNAs of genes involved in retinoic acid (RA) synthesis (Stra6 and Rdh10) were also increased by EtOH, AcH, and 4-HNE treatment. Retinoic acid receptor-c (RARc) is required for both EtOH-and AcH-mediated increases in Hoxa1 and Stra6, demonstrating the critical role of RA:RARc signaling in AcH-induced ESC differentiation.Conclusions: ACSS2 knockouts showed no changes in differentiation phenotype, while pluripotency-related transcripts were decreased in ALDH2 knockout ESCs. We demonstrate that AcH increases differentiation-associated mRNAs in ESCs via RARc.

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Section: Discussionmentioning

confidence: 99%

Different Effects of Knockouts in ALDH2 and ACSS2 on Embryonic Stem Cell Differentiation

Serio

Gross

et al. 2019

Alcoholism Clin & Exp Res

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“…Upon RES liberation, sensor proteins responsive to a given RES have to rapidly intercept the RES prior to diffusion and/or degradation/metabolism (Liu et al, 2019). Thus, the concept underlying REX technologies is unusual in that it harnesses intrinsic “reactivity/affinity-matching” between the released ligand and (a) POI(s) (Long and Aye, 2016, 2017; Long et al, 2016, 2017c; Parvez et al, 2018; Poganik et al, 2018; Liu et al, 2019). HaloTag-targetable photocaged probes such as Ht-PreHNE (1–20 μM) are tolerated by cells for > 2 h, and worms/developing fish for several days (Parvez et al, 2016; Long et al, 2017a,b, 2018a; Hall-Beauvais et al, 2018; Surya et al, 2018; Zhao et al, 2018).…”

Section: Comparison With Classical Methods To Understand Localizationmentioning

confidence: 99%

“…Thus, T-REX has established that some proteins are wired to react rapidly with HNE and to modulate signaling at fractional occupancy. We have dubbed such proteins privileged first responders (PFRs) (Long and Aye, 2017; Parvez et al, 2018; Poganik et al, 2018; Zhao et al, 2018; Liu et al, 2019). Using T-REX, HNEylation, at individual protein-specific levels, has been shown to impact numerous critical signaling subsystems and pathway intersections, including ubiquitination (Zhao et al, 2018) and phosphorylation (Long et al, 2017b).…”

Section: Comparison With Classical Methods To Understand Localizationmentioning

confidence: 99%

“…G-REX has as yet not been so applied. T-REX was used in fish embryos to study the effects of HNEylation of two different sensor proteins, Ube2V2 (Poganik et al, 2018; Zhao et al, 2018) and Akt3 (Long and Aye, 2017; Long et al, 2017b). It was noted that in these systems, expression of the transgenes was similar to that of the endogenous proteins (Long et al, 2017b; Zhao et al, 2018), rendering the systems more “natural” than that in cultured cells where the level of Halo-POI-overexpression was significant.…”

Section: Comparison With Classical Methods To Understand Localizationmentioning

confidence: 99%

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Chemical Biology Gateways to Mapping Location, Association, and Pathway Responsivity

2019

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Here we discuss, how by applying chemical concepts to biological problems, methods have been developed to map spatiotemporal regulation of proteins and small-molecule modulation of proteome signaling responses. We outline why chemical-biology platforms are ideal for such purposes. We further discuss strengths and weaknesses of chemical-biology protocols, contrasting them against classical genetic and biochemical approaches. We make these evaluations based on three parameters: occupancy; functional information; and spatial restriction. We demonstrate how the specific choice of chemical reagent and experimental set-up unite to resolve biological problems. Potential improvements/extensions as well as specific controls that in our opinion are often overlooked or employed incorrectly are also considered. Finally, we discuss some of the latest emerging methods to illuminate how chemical-biology innovations provide a gateway toward information hitherto inaccessible by conventional genetic/biochemical means. Finally, we also caution against solely relying on chemical-biology strategies and urge the field to undertake orthogonal validations to ensure robustness of results.

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“…Indeed, Poganik el al. [52] have recently compiled evidence to propose that native reactive electrophiles (e.g., 4-hydroxyalkenals) are signaling molecules. Moreover, some of these intracellular interactions were found to evoke hormetic responses that induced or augmented cellular defense mechanisms that ultimately enhance the elimination of the same electrophiles [12,23,51,53,54,55,56,57].…”

Section: Phospholipid Turnover In Cellsmentioning

confidence: 99%

The Combination of Whole Cell Lipidomics Analysis and Single Cell Confocal Imaging of Fluidity and Micropolarity Provides Insight into Stress-Induced Lipid Turnover in Subcellular Organelles of Pancreatic Beta Cells

et al. 2019

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Modern omics techniques reveal molecular structures and cellular networks of tissues and cells in unprecedented detail. Recent advances in single cell analysis have further revolutionized all disciplines in cellular and molecular biology. These methods have also been employed in current investigations on the structure and function of insulin secreting beta cells under normal and pathological conditions that lead to an impaired glucose tolerance and type 2 diabetes. Proteomic and transcriptomic analyses have pointed to significant alterations in protein expression and function in beta cells exposed to diabetes like conditions (e.g., high glucose and/or saturated fatty acids levels). These nutritional overload stressful conditions are often defined as glucolipotoxic due to the progressive damage they cause to the cells. Our recent studies on the rat insulinoma-derived INS-1E beta cell line point to differential effects of such conditions in the phospholipid bilayers in beta cells. This review focuses on confocal microscopy-based detection of these profound alterations in the plasma membrane and membranes of insulin granules and lipid droplets in single beta cells under such nutritional load conditions.

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Getting the Message? Native Reactive Electrophiles Pass Two Out of Three Thresholds to be Bona Fide Signaling Mediators

Cited by 19 publications

References 113 publications

Different Effects of Knockouts in ALDH2 and ACSS2 on Embryonic Stem Cell Differentiation

Different Effects of Knockouts in ALDH2 and ACSS2 on Embryonic Stem Cell Differentiation

Chemical Biology Gateways to Mapping Location, Association, and Pathway Responsivity

The Combination of Whole Cell Lipidomics Analysis and Single Cell Confocal Imaging of Fluidity and Micropolarity Provides Insight into Stress-Induced Lipid Turnover in Subcellular Organelles of Pancreatic Beta Cells

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