RNA-Binding Protein HuD Controls Insulin Translation

Laboratory of Molecular Biology and Immunology, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
Molecular cell (Impact Factor: 14.02). 02/2012; 45(6):826-35. DOI: 10.1016/j.molcel.2012.01.016
Source: PubMed


Although expression of the mammalian RNA-binding protein HuD was considered to be restricted to neurons, we report that HuD is present in pancreatic β cells, where its levels are controlled by the insulin receptor pathway. We found that HuD associated with a 22-nucleotide segment of the 5' untranslated region (UTR) of preproinsulin (Ins2) mRNA. Modulating HuD abundance did not alter Ins2 mRNA levels, but HuD overexpression decreased Ins2 mRNA translation and insulin production, and conversely, HuD silencing enhanced Ins2 mRNA translation and insulin production. Following treatment with glucose, HuD rapidly dissociated from Ins2 mRNA and enabled insulin biosynthesis. Importantly, HuD-knockout mice displayed higher insulin levels in pancreatic islets, while HuD-overexpressing mice exhibited lower insulin levels in islets and in plasma. In sum, our results identify HuD as a pivotal regulator of insulin translation in pancreatic β cells.

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Available from: Wook Kim
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    • "Indeed, RNA-binding proteins play a crucial role in gene expression control in all organisms. In eukaryotic cells, a large variety of ribonucleoprotein complexes affect the processing, transport, localization, translation and decay of mRNAs [30,31]. Thus, RNA-binding proteins are responsible for the establishment and regulation of RNA–protein networks that determine the target mRNA fate. "
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    • "Prior to our study, only two transcriptional mechanisms were known to regulate expression of the HuD gene—thyroid hormone (T3; presumably via activation of the thyroid hormone receptor) and TF forkhead box O1 (FoxO1)—and both of these factors were shown to negatively impact the abundance of HuD. T3 was demonstrated to decrease HuD mRNA synthesis in neuronal N2a cells, and T3 levels were inversely correlated with HuD mRNA levels in the rat brain (Cuadrado et al. 2003), whereas FoxO1 was recently found to negatively regulate transcription of HuD under low glucose conditions in pancreatic β cells (Lee et al. 2012). These findings raise the possibility that one or both of these transcriptional events maintain low/inhibit HuD expression in nonneuronal and neuronal precursor/stem cells. "
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    ABSTRACT: Precise control of messenger RNA (mRNA) processing and abundance are increasingly being recognized as critical for proper spatiotemporal gene expression, particularly in neurons. These regulatory events are governed by a large number of trans-acting factors found in neurons, most notably RNA-binding proteins (RBPs) and micro-RNAs (miRs), which bind to specific cis-acting elements or structures within mRNAs. Through this binding mechanism, trans-acting factors, particularly RBPs, control all aspects of mRNA metabolism, ranging from altering the transcription rate to mediating mRNA degradation. In this context the best-characterized neuronal RBP, the Hu/ELAVl family member HuD, is emerging as a key component in multiple regulatory processes-including pre-mRNA processing, mRNA stability, and translation-governing the fate of a substantial amount of neuronal mRNAs. Through its ability to regulate mRNA metabolism of diverse groups of functionally similar genes, HuD plays important roles in neuronal development and function. Furthermore, compelling evidence indicates supplementary roles for HuD in neuronal plasticity, in particular, recovery from axonal injury, learning and memory, and multiple neurological diseases. The purpose of this review is to provide a detailed overview of the current knowledge surrounding the expression and roles of HuD in the nervous system. Additionally, we outline the present understanding of the molecular mechanisms presiding over the localization, abundance, and function of HuD in neurons.
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    • "HuR (ELAVL1) is widely expressed and plays roles in DNA damage response, negative regulation of apoptosis, response to hypoxia, carcinogenesis, inflammation and several other diseases (1–8). The other family members, HuB (ELAVL2), HuC (ELAVL3) and HuD (ELAVL4), are neuron-enriched and play roles in neuronal differentiation, neuronal maintenance, learning, memory and regulation of neuronal excitability, as well as roles outside of the nervous system, including regulation of insulin translation in pancreatic β cells by HuD (7,9–13). On a molecular level, Hu proteins bind to U-rich (AU or GU) sequences in RNA targets and regulate RNA metabolism through diverse mechanisms (7,10,13–16). "
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