HuR Enhances Early Restitution of the Intestinal Epithelium by Increasing Cdc42 Translation

et al. 2018

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The mammalian intestinal epithelium establishes a selectively permeable barrier that supports nutrient absorption and prevents intrusion by noxious luminal substances and microbiota. The effectiveness and integrity of the barrier function are tightly regulated via well-controlled mechanisms. Long noncoding RNAs transcribed from ultraconserved regions (T-UCRs) control diverse cellular processes, but their roles in the regulation of gut permeability remain largely unknown. Here we report that the T-UCR enhances intestinal epithelial barrier function by antagonizing microRNA 29b (miR-29b). Decreasing the levels of by gene silencing led to dysfunction of the intestinal epithelial barrier in cultured cells and increased the vulnerability of the gut barrier to septic stress in mice. specifically stimulated translation of the tight junction (TJ) claudin-1 (CLDN1) by associating with miR-29b rather than by binding directly to mRNA. acted as a natural decoy RNA for miR-29b, which interacts with mRNA via the 3' untranslated region and represses its translation. Ectopically expressed abolished the association of miR-29b with mRNA and restored claudin-1 expression to normal levels in cells overexpressing miR-29b, thus rescuing the barrier function. These results highlight a novel function of in controlling gut permeability and define a mechanism by which stimulates claudin-1 translation, by decreasing the availability of miR-29b to mRNA.

Section: Methodsmentioning

confidence: 99%

Regulation of Intestinal Epithelial Barrier Function by Long Noncoding RNA uc.173 through Interaction with MicroRNA 29b

Wang

Cui

et al. 2018

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“…To examine changes in ␣4 expression in response to the stressful environment in IECs, we employed a previously described (5) in vitro repair model that mimics the early cell division-independent stage of intestinal epithelial restitution. As reported previously (5,23), epithelial restitution occurred rapidly after wounding, as revealed by a significant increase in cell migration over the wounded area by 6 h (data not shown). Interestingly, the levels of ␣4 protein increased remarkably 1 h after wounding and remained elevated for an additional 5 h (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Paneth cells, which secrete antibacterial peptides and growth factors, however, reside at the base of the crypt area of the intestinal mucosa. The maintenance of apical-basal polarity of intestinal epithelial cells (IECs) depends on a dynamic balance among multiple cellular activities, including proliferation, differentiation, migration, and apoptosis, that are tightly regulated by distinct signaling networks (4,5). Disruption of the integrity of the intestinal epithelium occurs commonly in various critical pathological conditions, leading to the translocation of luminal toxic substances and bacteria to the bloodstream and, in some instances, multiple-organ dysfunction syndromes and death (6,7).…”

mentioning

confidence: 99%

“…For example, despite the proliferative influence of the small GTPase Cdc42 (18), its targeted deletion in IECs resulted in gross hyperplasia of the intestinal epithelium, crypt enlargement, microvillus inclusion, and increased gut permeability (19). Similarly, intestinal epithelium-specific deletion of the RNA-binding protein (RBP) HuR (ELAVL1), which promotes division in cultured cells (20), caused significant mucosal atrophy in the small intestine and decreased the regenerative potential of crypt progenitors after injury (5,21). In other cases, mouse studies and cultured cell studies agree; for example, expression of the microRNA miR-222 inhibits growth of cultured IECs and delays the repair of damaged mucosa in mice (22).…”

mentioning

confidence: 99%

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α4 Coordinates Small Intestinal Epithelium Homeostasis by Regulating Stability of HuR

Chung

Wang

et al. 2018

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The mammalian intestinal epithelium is a rapidly self-renewing tissue in the body, and its homeostasis depends on a dynamic balance among proliferation, migration, apoptosis, and differentiation of intestinal epithelial cells (IECs). The protein phosphatase 2A (PP2A)-associated protein α4 controls the activity and specificity of serine/threonine phosphatases and is thus implicated in many cellular processes. Here, using a genetic approach, we investigated the mechanisms whereby α4 controls the homeostasis of the intestinal epithelium. In mice with ablated α4, the small intestinal mucosa exhibited crypt hyperplasia, villus shrinkage, defective differentiation of Paneth cells, and reduced IEC migration along the crypt-villus axis. The α4-deficient intestinal epithelium also displayed decreased expression of different intercellular junction proteins and abnormal epithelial permeability. In addition, α4 deficiency decreased the levels of the RNA-binding protein HuR in the mucosal tissue. In cultured IECs, ectopic overexpression of HuR in α4-deficient cells rescued the production of these intercellular junction proteins and restored the epithelial barrier function to a nearly normal level. Mechanistically, α4 silencing destabilized HuR through a process involving HuR phosphorylation by IκB kinase α, leading to ubiquitin-mediated proteolysis of HuR. These findings indicate that the critical impact of α4 upon the barrier function and homeostasis of the intestinal epithelium depends largely on its ability to regulate the stability of HuR.

“…The cooperative inhibition of IGF2R expression by CUGBP1 and miR-195 was not surprising, as several studies showed that CUGBP1 functionally interacts with miRNAs and/or other RBPs to remodel ribonucleoprotein complexes and influence the posttranscriptional fate of mRNAs positively or negatively (14,37). For example, CUGBP1 interacts with miR-222 to inhibit translation of the Cdk4 mRNA synergistically (18), but it competes with HuR to regulate translation of the tight junction occludin and transcription factor MYC antagonistically (25,26).…”

Section: Discussionmentioning

confidence: 99%

Cooperative Repression of Insulin-Like Growth Factor Type 2 Receptor Translation by MicroRNA 195 and RNA-Binding Protein CUGBP1

Zhang

et al. 2017

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Insulin-like growth factor type 2 (IGF2) receptor (IGF2R) recognizes mannose 6-phosphate-containing molecules and IGF2 and plays an important role in many pathophysiological processes, including gut mucosal adaptation. However, the mechanisms that control cellular IGF2R abundance are poorly known. MicroRNAs (miRNAs) and RNA-binding proteins (RBPs) critically regulate gene expression programs in mammalian cells by modulating the stability and translation of target mRNAs. Here we report that miRNA 195 (miR-195) and RBP CUG-binding protein 1 (CUGBP1) jointly regulate IGF2R expression at the posttranscriptional level in intestinal epithelial cells. Both miR-195 and CUGBP1 interacted with the 3= untranslated region (3=-UTR) of Igf2r mRNA, and the association of CUGBP1 with Igf2r mRNA enhanced miR-195 binding to Igf2r mRNA. Ectopically expressed CUGBP1 and miR-195 repressed IGF2R translation cooperatively without altering the stability of Igf2r mRNA. Importantly, the miR-195-and CUGBP1-repressed levels of cellular IGF2R led to a disruption in the structure of the trans-Golgi network. These findings indicate that IGF2R expression is controlled posttranscriptionally by two factors that associate with Igf2r mRNA and suggest that miR-195 and CUGBP1 dampen IGF signaling by inhibiting IGF2R translation.KEYWORDS insulin superfamily, posttranscriptional regulation, trans-Golgi network, intestinal epithelial cells, RNA-binding proteins, noncoding RNAs M ucosal regeneration/adaptation is an essential process in gut homeostasis and tightly regulated by numerous factors, including insulin-like growth factor type 1 (IGF1) and IGF2 (1, 2). Two structurally distinct types of receptors, the IGF1 receptor (IGF1R) and IGF2R, specifically interact with IGF1 and IGF2 as ligands and regulate diverse biological functions such as cell proliferation, differentiation, and apoptosis (3, 4). Like the insulin receptor, IGF1R is a heterotetrameric transmembrane receptor tyrosine kinase, and its activation results in autophosphorylation of tyrosine residues in the intracellular ␤-subunits, thus initiating the phosphatidylinositol 3-kinase (PI3) kinase/AKT and/or mitogen-activated protein (MAP) kinase signaling cascade (5). In contrast, IGF2R is a single-transmembrane-domain protein and binds IGF2 with greater affinity than IGF1, although it does not accept insulin as a ligand (4, 6). IGF2R also recognizes, via distinct sites, mannose-6-phosphate (M6P)-containing molecules and can therefore associate with other growth factors and cytokines (4). The majority of IGF2R is localized in the trans-Golgi network (TGN) and endosomal compartments and, to a lesser extent, on the cell surface (6). A subpopulation of the IGF2R on the plasma membrane regulates IGF2 internalization and various M6P-containing ligands for their