Oligomeric transition and dynamics of RNA binding by the HuR RRM1 domain in solution

Lixa, Carolina; Mujo, Amanda; Magalhães, Mariana T.Q. de; Almeida, Fábio C. L.; Lima, L.M.T.R.; Pinheiro, Anderson S.

doi:10.1007/s10858-018-0217-y

Cited by 13 publications

(12 citation statements)

References 70 publications

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“…HuR is a multidomain protein harboring a total of three cysteines ( Figure ,A ), one of which (C13) resides close to the unstructured N‐terminus, and two of which (C245 and C284), also appear to be solvent accessible, at least based on crystal and NMR solution structures of the RRM3 domain wherein these two cysteines reside ( Figure ,B ) . Cysteine 13 (C13) of human HuR has been previously proposed to act as a redox sensor that functions through formation of a disulfide bridge between two molecules of HuR.…”

Section: Resultsmentioning

confidence: 99%

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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Section: Resultsmentioning

confidence: 99%

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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“…RNA-binding proteins usually function as major posttranscriptional regulators by RNA-binding activities [15]. Heterogeneous nuclear ribonucleoprotein C (C1/ C2), also known as hnRNPC, belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs).…”

Section: Introductionmentioning

confidence: 99%

Knockdown of LINC00662 represses AK4 and attenuates radioresistance of oral squamous cell carcinoma

et al. 2020

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Background: LncRNAs play crucial roles in the development of carcinomas. However, the investigation of LINC00662 in Oral squamous cell carcinoma (OSCC) is still elusive. Methods: qRT-PCR assay tested the expression levels of LINC00662, hnRNPC and AK4. With exposure to irradiation, CCK-8, colony formation, flow cytometry and western blot experiments, respectively determined the function of LINC00662 in the radiosensitivity of OSCC cells. Then RIP and western blot assays affirmed the interaction between hnRNPC protein and LINC00662 or AK4. Finally, rescue assays validated the regulation mechanism of LINC00662 in the radioresistance of OSCC. Results: In the present report, LINC00662 was overexpressed in OSCC and its silencing could alleviate radioresistance of OSCC. Furthermore, the interaction between hnRNPC protein and LINC00662 or AK4 was uncovered. Besides, LINC00662 regulated AK4 mRNA stability through binding to hnRNPC protein. To sum up, LINC00662 modulated the radiosensitivity of OSCC cells via hnRNPC-modulated AK4. Conclusion: The molecular mechanism of the LINC00662/hnRNPC/AK4 axis was elucidated in OSCC, which exhibited a promising therapeutic direction for patients with OSCC.

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“…HuR is a multidomain protein harboring a total of 3 cysteines (Figure 2A), one of which (C13) resides close to the unstructured N-terminus, [30] and two of which (C245 and C284), also appear to be solvent accessible, at least based on crystal and NMR solution structures of the RRM3 domain wherein these two cysteines reside ( Figure 2B). [31][32][33] Cysteine 13 (C13) of human HuR has been previously proposed to act as a redox sensor that functions through formation of a disulfide bridge between two molecules of HuR.…”

Section: Hur Senses Hne Specifically Through C13mentioning

confidence: 99%

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.

show abstract

Oligomeric transition and dynamics of RNA binding by the HuR RRM1 domain in solution

Cited by 13 publications

References 70 publications

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

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

Knockdown of LINC00662 represses AK4 and attenuates radioresistance of oral squamous cell carcinoma

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

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