Nucleophosmin Is Essential for Stimulation of Rac1 Nuclear Accumulation by RNA‐binding Protein HuR in the Intestinal Epithelium

Inhibition of growth of the intestinal epithelium, a rapidly self-renewing tissue, is commonly found in various critical disorders. The RNA-binding protein HuR is highly expressed in the gut mucosa and modulates the stability and translation of target mRNAs, but its exact biological function in the intestinal epithelium remains unclear. Here, we investigated the role of HuR in intestinal homeostasis using a genetic model and further defined its target mRNAs. Targeted deletion of HuR in intestinal epithelial cells caused significant mucosal atrophy in the small intestine, as indicated by decreased cell proliferation within the crypts and subsequent shrinkages of crypts and villi. In addition, the HuR-deficient intestinal epithelium also displayed decreased regenerative potential of crypt progenitors after exposure to irradiation. HuR deficiency decreased expression of the Wnt coreceptor LDL receptor–related protein 6 (LRP6) in the mucosal tissues. At the molecular level, HuR was found to bind the Lrp6 mRNA via its 3′-untranslated region and enhanced LRP6 expression by stabilizing Lrp6 mRNA and stimulating its translation. These results indicate that HuR is essential for normal mucosal growth in the small intestine by altering Wnt signals through up-regulation of LRP6 expression and highlight a novel role of HuR deficiency in the pathogenesis of intestinal mucosal atrophy under pathological conditions.

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RNA-Binding Protein HuR Regulates Rac1 Nucleocytoplasmic Shuttling Through Nucleophosmin in the Intestinal Epithelium

Cellular and Molecular Gastroenterology and Hepatology ◽

10.1016/j.jcmgh.2019.06.002 ◽

2019 ◽

Vol 8 (3) ◽

pp. 475-486 ◽

Cited By ~ 3

Author(s):

Lan Liu ◽

Lan Xiao ◽

Hee K. Chung ◽

Min S. Kwon ◽

Xiao-Xue Li ◽

...

Keyword(s):

Intestinal Epithelium ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Nucleocytoplasmic Shuttling

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RNA-binding protein HuR regulates translation of vitamin D receptor modulating rapid epithelial restitution after wounding

AJP Cell Physiology ◽

10.1152/ajpcell.00009.2020 ◽

2020 ◽

Vol 319 (1) ◽

pp. C208-C217

Author(s):

Yunzhan Zhang ◽

Jia-Zhong Cai ◽

Lan Xiao ◽

Hee K. Chung ◽

Xiang-Xue Ma ◽

...

Keyword(s):

Vitamin D ◽

Vitamin D Receptor ◽

Intestinal Mucosa ◽

Intestinal Epithelium ◽

Rna Binding ◽

Ex Vivo ◽

Binding Protein ◽

Rna Binding Protein ◽

Intestinal Epithelial ◽

Epithelial Restitution

Homeostasis of the intestinal epithelium is tightly regulated by numerous extracellular and intracellular factors including vitamin D and the vitamin D receptor (VDR). VDR is highly expressed in the intestinal epithelium and is implicated in many aspects of gut mucosal pathophysiology, but the exact mechanism that controls VDR expression remains largely unknown. The RNA-binding protein human antigen R (HuR) regulates the stability and translation of target mRNAs and thus modulates various cellular processes and functions. Here we report a novel role of HuR in the posttranscriptional control of VDR expression in the intestinal epithelium. The levels of VDR in the intestinal mucosa decreased significantly in mice with ablated HuR, compared with control mice. HuR silencing in cultured intestinal epithelial cells (IECs) also reduced VDR levels, whereas HuR overexpression increased VDR abundance; neither intervention changed cellular Vdr mRNA content. Mechanistically, HuR bound to Vdr mRNA via its 3′-untranslated region (UTR) and enhanced VDR translation in IECs. Moreover, VDR silencing not only inhibited IEC migration over the wounded area in control cells but also prevented the increased migration in cells overexpressing HuR, although it did not alter IEC proliferation in vitro and growth of intestinal organoids ex vivo. The human intestinal mucosa from patients with inflammatory bowel diseases exhibited decreased levels of both HuR and VDR. These results indicate that HuR enhances VDR translation by directly interacting with its mRNA via 3′-UTR and that induced VDR by HuR is crucial for rapid intestinal epithelial restitution after wounding.

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Tu1856 - RNA-Binding Protein Hur Regulates Autophagy Activity by Altering TLR2 Subcellular Distribution in the Intestinal Epithelium

Gastroenterology ◽

10.1016/s0016-5085(18)33482-6 ◽

2018 ◽

Vol 154 (6) ◽

pp. S-1039

Author(s):

Lan Xiao ◽

Yunzhan Zhang ◽

Sudhakar Kalakonda ◽

Hee Kyoung Chung ◽

Tingxi Yu ◽

...

Keyword(s):

Intestinal Epithelium ◽

Subcellular Distribution ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Autophagy Activity

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RNA-binding protein HuR mediates cytoprotection through stimulation of XIAP translation

Oncogene ◽

10.1038/onc.2010.527 ◽

2010 ◽

Vol 30 (12) ◽

pp. 1460-1469 ◽

Cited By ~ 55

Author(s):

D Durie ◽

S M Lewis ◽

U Liwak ◽

M Kisilewicz ◽

M Gorospe ◽

...

Keyword(s):

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Stimulation Of

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MECHANISMS OF TRANSLATIONAL CONTROL OF APOLIPOPROTEIN B MRNA: IDENTIFICATION OF A NOVEL, INSULIN-SENSITIVE 110 KDA RNA BINDING PROTEIN MEDIATING TRANSLATIONAL STIMULATION OF APOLIPOPROTEIN B MRNA VIA CIS-TRANS INTERACTIONS AT THE 5′ UTR

Cardiovascular Pathology ◽

10.1016/j.carpath.2004.03.383 ◽

2004 ◽

Vol 13 (3) ◽

pp. 127

Author(s):

Konstantinos Gus Sidiropoulos ◽

Louisa Pontrelli ◽

Khosrow Adeli

Keyword(s):

Translational Control ◽

Apolipoprotein B ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Stimulation Of

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The RNA-Binding Protein ELAVL1 Regulates GnRH Receptor Expression and the Response to GnRH

Endocrinology ◽

10.1210/en.2019-00203 ◽

2019 ◽

Vol 160 (8) ◽

pp. 1999-2014 ◽

Cited By ~ 3

Author(s):

Tomohiro Terasaka ◽

Taeshin Kim ◽

Hiral Dave ◽

Bhakti Gangapurkar ◽

Dequina A Nicholas ◽

...

Keyword(s):

Gene Expression ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Gnrh Receptor ◽

Receptor Expression ◽

Cell Surface Expression ◽

Mrna Levels ◽

Lh Secretion ◽

Stimulation Of

Abstract Gonadotropin secretion, which is elicited by GnRH stimulation of the anterior pituitary gonadotropes, is a critical feature of reproductive control and the maintenance of fertility. In addition, activation of the GnRH receptor (GnRHR) regulates transcription and translation of multiple factors that regulate the signaling response and synthesis of gonadotropins. GnRH stimulation results in a broad redistribution of mRNA between active and inactive polyribosomes within the cell, but the mechanism of redistribution is not known. The RNA-binding protein embryonic lethal, abnormal vision, Drosophila-like 1 (ELAVL1) binds to AU-rich elements in mRNA and is one of the most abundant mRNA-binding proteins in eukaryotic cells. It is known to serve as a core component of RNA-binding complexes that direct the fate of mRNA. In LβT2 gonadotropes, we showed that ELAVL1 binds to multiple mRNAs encoding factors that are crucial for gonadotropin synthesis and release. Association with some mRNAs is GnRH sensitive but does not correlate with abundance of binding. We also showed MAPK-dependent changes in intracellular localization of ELAVL1 in response to GnRH stimulation. Knockdown of ELAVL1 gene expression resulted in reduced Lhb and Gnrhr mRNA levels, reduced cell surface expression of GnRHR, and reduced LH secretion in response to GnRH stimulation. Overall, these observations not only support the role of ELAVL1 in GnRHR-mediated regulation of gene expression and LH secretion but also indicate that other factors may contribute to the precise fate of mRNA in response to GnRH stimulation of gonadotropes.

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