Post‐transcriptional regulation of Nrf2‐mRNA by the mRNA‐binding proteins HuR and AUF1

Poganik, Jesse R.; Long, Marcus J. C.; Disare, Michael T.; Liu, Xuyu; Chang, Sung-Hee; Hla, Timothy; Aye, Yimon

doi:10.1096/fj.201901930r

Cited by 50 publications

(64 citation statements)

References 72 publications

(118 reference statements)

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“…Thus, HuR knockdown affects cellular sensitivity to redox stress, at least as significantly as, and in some cases more than, knockdown of Nrf2, a protein that is believed to be essential to protect against various small-molecule stressors. Consistent with this notion, AR levels (which directly and faithfully report on levels of active Nrf2 [21] ) were consistently upregulated by ~2-fold in cells transfected with siHuR and treated with HNE, compared to siControl-transfected cells ( Figure 4E). No modulation of AR was observed on average in cells transfected with siHuR and exposed to H2O2 ( Figure 4F).…”

Section: Hur Senses Hne Specifically Through C13supporting

confidence: 72%

“…This effect ultimately transpired to not be fully explained by modification of HuR(C13), although there was a significant difference in response between cells expressing wild type HuR and HuR(C13S). Collectively, these observations add an unexpected layer of complexity to a HuR-AR regulatory program we recently reported, [21] and point to a means to covalently target HuR, orthogonal to AUF1, in future drug discovery endeavors.…”

Section: Introductionmentioning

confidence: 55%

“…Importantly, AR levels in non-treated cells were significantly suppressed when HuR was knocked down, validating HuR knockdown ( Figure 4G). [21] We note that the antagonistic effects of HuR-knockdown cells under non-treated conditions (AR suppressed) versus HNE-treated conditions (AR hyperstimulated) reflects the pleiotropic nature of both electrophiles and HuR.…”

Section: Hur Senses Hne Specifically Through C13mentioning

confidence: 85%

“…HuR(C13S) was unable to sense HNE both in vitro and in cells. We further found HuR-dependent modulation of Nrf2/antioxidant response (AR)-a key cell defense pathway regulated by HuR [21] -upon stimulation of cells with HNE. This effect ultimately transpired to not be fully explained by modification of HuR(C13), although there was a significant difference in response between cells expressing wild type HuR and HuR(C13S).…”

Section: Introductionmentioning

confidence: 83%

“…[47] We have also recently shown that expression levels of Nrf2 and response to electrophilic stress are regulated by HuR expression. [21] Knockdown of Nrf2 also rendered cells around 20% more sensitive to HNE ( Figure 4C). However, we observed no difference in EC50 for growth inhibition by H2O2 ( Figure 4D).…”

Section: Hur Senses Hne Specifically Through C13mentioning

confidence: 90%

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The mRNA-binding protein HuR is a kinetically-privileged electrophile sensor

Poganik

Hall-Beauvais

Long

et al. 2020

Preprint

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AbstractThe key mRNA-binding proteins HuR and AUF1 are reported stress sensors in mammals. Intrigued by recent reports of sensitivity of these proteins to the electrophilic lipid prostaglandin A2 and other redox signals, we here examined their sensing abilities to a prototypical redox-linked lipid-derived electrophile, 4-hydroxynonenal (HNE). Leveraging our T-REX electrophile delivery platform, we found that only HuR, and not AUF1, is a kinetically-privileged sensor of HNE in HEK293T cells, and sensing functions through a specific cysteine, C13. Cells depleted of HuR, upon treatment with HNE, manifest unique alterations in cell viability and Nrf2-transcription-factor-driven antioxidant response (AR), which our recent work shows is regulated by HuR at the Nrf2-mRNA level. Mutagenesis studies showed that C13-specific sensing alone is not sufficient to explain HuR-dependent stress responsivities, further highlighting a complex context-dependent layer of Nrf2/AR regulation through HuR.

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Section: Hur Senses Hne Specifically Through C13supporting

confidence: 72%

Section: Introductionmentioning

confidence: 55%

Section: Hur Senses Hne Specifically Through C13mentioning

confidence: 85%

Section: Introductionmentioning

confidence: 83%

Section: Hur Senses Hne Specifically Through C13mentioning

confidence: 90%

See 3 more Smart Citations

The mRNA-binding protein HuR is a kinetically-privileged electrophile sensor

Poganik

Hall-Beauvais

Long

et al. 2020

Preprint

Self Cite

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Climbing into their Skin to Understand Contextual Protein–Protein Associations and Localizations: Functional Investigations in Transgenic Live Model Organisms

Long,

Aye

2024

ChemBioChem

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Borrowing some quotes from Harper Lee's novel “To Kill A Mockingbird” to help frame our manuscript, we discuss methods to profile local proteomes. We initially focus on chemical biology regimens that function in live organisms and use reactive biotin species for this purpose. We then consider ways to add new dimensions to these experimental regimens, principally by releasing less reactive (i. e., more selective) (preter)natural electrophiles. Although electrophile release methods may have lower resolution and label fewer proteins than biotinylation methods, their ability to probe simultaneously protein function and locale raises new and interesting possibilities for the field.

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The mRNA‐Binding Protein HuR Is a Kinetically‐Privileged Electrophile Sensor

Poganik

Hall-Beauvais

Long

et al. 2020

Helvetica Chimica Acta

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Dedicated to career of and contributions by Prof. Dr. Michael Graetzel (ISIC, EPFL) on his 75 th birthdayThe key mRNA-binding proteins HuR and AUF1 are reported stress sensors in mammals. Intrigued by recent reports of sensitivity of these proteins to the electrophilic lipid prostaglandin A2 and other redox signals, we here examined their sensing abilities to a prototypical redox-linked lipid-derived electrophile, 4-hydroxynonenal (HNE). Leveraging our T-REX electrophile delivery platform, we found that only HuR, and not AUF1, is a kinetically-privileged sensor of HNE in HEK293T cells, and sensing functions through a specific cysteine, C13. Cells depleted of HuR, upon treatment with HNE, manifest unique alterations in cell viability and Nrf2transcription-factor-driven antioxidant response (AR), which our recent work shows is regulated by HuR at the Nrf2-mRNA level. Mutagenesis studies showed that C13-specific sensing alone is not sufficient to explain HuRdependent stress responsivities, further highlighting a complex context-dependent layer of Nrf2/AR regulation through HuR. Figure 1. HuR, but not AUF1, is a sensor of HNE in HEK293T cells. A) Structures of the native RES prostaglandin A2 (PGA2) and alkyne-functionalized HNE. B) HEK293T cells were treated with HNE(alkyne) (20 μM, 18 h). Click chemistry was used to biotinylate HNE-modified proteins, which were then enriched with streptavidin resin. Shown is a representative blot from four independent experiments. Inset at right: Quantification (mean � SEM) of western blot data from n = 4 independent replicates. ND: not detected.

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Post‐transcriptional regulation of Nrf2‐mRNA by the mRNA‐binding proteins HuR and AUF1

Cited by 50 publications

References 72 publications

The mRNA-binding protein HuR is a kinetically-privileged electrophile sensor

The mRNA-binding protein HuR is a kinetically-privileged electrophile sensor

Climbing into their Skin to Understand Contextual Protein–Protein Associations and Localizations: Functional Investigations in Transgenic Live Model Organisms

The mRNA‐Binding Protein HuR Is a Kinetically‐Privileged Electrophile Sensor

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