hnRNP Q Regulates Internal Ribosome Entry Site-Mediated fmr1 Translation in Neurons

ABSTRACT Fragile X syndrome (FXS) caused by loss of fragile X mental retardation protein (FMRP), is the most common cause of inherited intellectual disability. Numerous studies show that FMRP is an RNA binding protein that regulates translation of its binding targets and plays key roles in neuronal functions. However, the regulatory mechanism for FMRP expression is incompletely understood. Conflicting results regarding internal ribosome entry site (IRES)-mediated fmr1 translation have been reported. Here, we unambiguously demonstrate that the fmr1 gene, which encodes FMRP, exploits both IRES-mediated translation and canonical cap-dependent translation. Furthermore, we find that heterogeneous nuclear ribonucleoprotein Q (hnRNP Q) acts as an IRES-transacting factor (ITAF) for IRES-mediated fmr1 translation in neurons. We also show that semaphorin 3A (Sema3A)-induced axonal growth cone collapse is due to upregulation of hnRNP Q and subsequent IRES-mediated expression of FMRP. These data elucidate the regulatory mechanism of FMRP expression and its role in axonal growth cone collapse.

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Faculty Opinions recommendation of The double-stranded RNA binding protein 76:NF45 heterodimer inhibits translation initiation at the rhinovirus type 2 internal ribosome entry site.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1033130.375126 ◽

2006 ◽

Author(s):

Lee Gehrke

Keyword(s):

Translation Initiation ◽

Internal Ribosome Entry Site ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Entry Site ◽

Internal Ribosome Entry ◽

Double Stranded Rna

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IL-6-Induced Stimulation of c-Myc Translation in Multiple Myeloma Cells Is Mediated by Myc Internal Ribosome Entry Site Function and the RNA-Binding Protein, hnRNP A1

Cancer Research ◽

10.1158/0008-5472.can-08-1066 ◽

2008 ◽

Vol 68 (24) ◽

pp. 10215-10222 ◽

Cited By ~ 50

Author(s):

Y. Shi ◽

P. J. Frost ◽

B. Q. Hoang ◽

A. Benavides ◽

S. Sharma ◽

...

Keyword(s):

Multiple Myeloma ◽

Internal Ribosome Entry Site ◽

Rna Binding ◽

Rna Binding Protein ◽

Hnrnp A1 ◽

Entry Site ◽

Internal Ribosome Entry ◽

Myeloma Cells ◽

Site Function ◽

Stimulation Of

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Efficient Translation Initiation Directed by the 900-Nucleotide-Long and GC-Rich 5′ Untranslated Region of the Human Retrotransposon LINE-1 mRNA Is Strictly Cap Dependent Rather than Internal Ribosome Entry Site Mediated

Molecular and Cellular Biology ◽

10.1128/mcb.02138-06 ◽

2007 ◽

Vol 27 (13) ◽

pp. 4685-4697 ◽

Cited By ~ 82

Author(s):

Sergey E. Dmitriev ◽

Dmitri E. Andreev ◽

Ilya M. Terenin ◽

Ivan A. Olovnikov ◽

Vladimir S. Prassolov ◽

...

Keyword(s):

Translation Initiation ◽

Internal Ribosome Entry Site ◽

Untranslated Region ◽

High Efficiency ◽

Rna Binding ◽

Cultured Cells ◽

Entry Site ◽

Internal Ribosome Entry ◽

Cellular Mrnas ◽

Internal Initiation

ABSTRACT Retrotransposon L1 is a mobile genetic element of the LINE family that is extremely widespread in the mammalian genome. It encodes a dicistronic mRNA, which is exceptionally rare among eukaryotic cellular mRNAs. The extremely long and GC-rich L1 5′ untranslated region (5′UTR) directs synthesis of numerous copies of RNA-binding protein ORF1p per mRNA. One could suggest that the 5′UTR of L1 mRNA contained a powerful internal ribosome entry site (IRES) element. Using transfection of cultured cells with the polyadenylated monocistronic (L1 5′UTR-Fluc) or bicistronic (Rluc-L1 5′UTR-Fluc) RNA constructs, capped or uncapped, it has been firmly established that the 5′UTR of L1 does not contain an IRES. Uncapping reduces the initiation activity of the L1 5′UTR to that of background. Moreover, the translation is inhibited by upstream AUG codons in the 5′UTR. Nevertheless, this cap-dependent initiation activity of the L1 5′UTR was unexpectedly high and resembles that of the beta-actin 5′UTR (84 nucleotides long). Strikingly, the deletion of up to 80% of the nucleotide sequence of the L1 5′UTR, with most of its stem loops, does not significantly change its translation initiation efficiency. These data can modify current ideas on mechanisms used by 40S ribosomal subunits to cope with complex 5′UTRs and call into question the conception that every long GC-rich 5′UTR working with a high efficiency has to contain an IRES. Our data also demonstrate that the ORF2 translation initiation is not directed by internal initiation, either. It is very inefficient and presumably based on a reinitiation event.

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RNA-binding Protein HuR Interacts with Thrombomodulin 5′Untranslated Region and Represses Internal Ribosome Entry Site–mediated Translation under IL-1β Treatment

Molecular Biology of the Cell ◽

10.1091/mbc.e07-09-0962 ◽

2008 ◽

Vol 19 (9) ◽

pp. 3812-3822 ◽

Cited By ~ 28

Author(s):

Chiu-Hung Yeh ◽

Liang-Yi Hung ◽

Chin Hsu ◽

Shu-Yun Le ◽

Pin-Tse Lee ◽

...

Keyword(s):

Protein Expression ◽

Internal Ribosome Entry Site ◽

Untranslated Region ◽

Protein C ◽

Rna Binding ◽

Activated Protein C ◽

Critical Factor ◽

Entry Site ◽

Internal Ribosome Entry ◽

Sepsis And Septic Shock

Reduction in host-activated protein C levels and resultant microvascular thrombosis highlight the important functional role of protein C anticoagulant system in the pathogenesis of sepsis and septic shock. Thrombomodulin (TM) is a critical factor to activate protein C in mediating the anticoagulation and anti-inflammation effects. However, TM protein content is decreased in inflammation and sepsis, and the mechanism is still not well defined. In this report, we identified that the TM 5′ untranslated region (UTR) bearing the internal ribosome entry site (IRES) element controls TM protein expression. Using RNA probe pulldown assay, HuR was demonstrated to interact with the TM 5′UTR. Overexpression of HuR protein inhibited the activity of TM IRES, whereas on the other hand, reducing the HuR protein level reversed this effect. When cells were treated with IL-1β, the IRES activity was suppressed and accompanied by an increased interaction between HuR and TM 5′UTR. In the animal model of sepsis, we found the TM protein expression level to be decreased while concurrently observing the increased interaction between HuR and TM mRNA in liver tissue. In summary, HuR plays an important role in suppression of TM protein synthesis in IL-1β treatment and sepsis.

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Plexin-B1/RhoGEF–mediated RhoA activation involves the receptor tyrosine kinase ErbB-2

The Journal of Cell Biology ◽

10.1083/jcb.200312094 ◽

2004 ◽

Vol 165 (6) ◽

pp. 869-880 ◽

Cited By ~ 99

Author(s):

Jakub M. Swiercz ◽

Rohini Kuner ◽

Stefan Offermanns

Keyword(s):

Tyrosine Kinase ◽

Growth Cone ◽

Receptor Tyrosine Kinase ◽

Hippocampal Neurons ◽

Molecular Mechanisms ◽

Axonal Growth ◽

Dominant Negative ◽

Growth Cone Collapse ◽

Rhoa Activation ◽

Axonal Growth Cone

Plexins are widely expressed transmembrane proteins that mediate the effects of semaphorins. The molecular mechanisms of plexin-mediated signal transduction are still rather unclear. Plexin-B1 has recently been shown to mediate activation of RhoA through a stable interaction with the Rho guanine nucleotide exchange factors PDZ-RhoGEF and LARG. However, it is unclear how the activity of plexin-B1 and its downstream effectors is regulated by its ligand Sema4D. Here, we show that plexin-B family members stably associate with the receptor tyrosine kinase ErbB-2. Binding of Sema4D to plexin-B1 stimulates the intrinsic tyrosine kinase activity of ErbB-2, resulting in the phosphorylation of both plexin-B1 and ErbB-2. A dominant-negative form of ErbB-2 blocks Sema4D-induced RhoA activation as well as axonal growth cone collapse in primary hippocampal neurons. Our data indicate that ErbB-2 is an important component of the plexin-B receptor system and that ErbB-2–mediated phosphorylation of plexin-B1 is critically involved in Sema4D-induced RhoA activation, which underlies cellular phenomena downstream of plexin-B1, including axonal growth cone collapse.

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Deconstructing internal ribosome entry site elements: an update of structural motifs and functional divergences

Open Biology ◽

10.1098/rsob.180155 ◽

2018 ◽

Vol 8 (11) ◽

pp. 180155 ◽

Cited By ~ 7

Author(s):

Gloria Lozano ◽

Rosario Francisco-Velilla ◽

Encarnacion Martinez-Salas

Keyword(s):

Internal Ribosome Entry Site ◽

Rna Structure ◽

Rna Binding ◽

Building Blocks ◽

Regulatory Elements ◽

Entry Site ◽

Internal Ribosome Entry ◽

Ribonucleoprotein Complexes ◽

Structure Conservation ◽

Initiation Of Translation

Beyond the general cap-dependent translation initiation, eukaryotic organisms use alternative mechanisms to initiate protein synthesis. Internal ribosome entry site (IRES) elements are cis -acting RNA regions that promote internal initiation of translation using a cap-independent mechanism. However, their lack of primary sequence and secondary RNA structure conservation, as well as the diversity of host factor requirement to recruit the ribosomal subunits, suggest distinct types of IRES elements. In spite of this heterogeneity, conserved motifs preserve sequences impacting on RNA structure and RNA–protein interactions important for IRES-driven translation. This conservation brings the question of whether IRES elements could consist of basic building blocks, which upon evolutionary selection result in functional elements with different properties. Although RNA-binding proteins (RBPs) perform a crucial role in the assembly of ribonucleoprotein complexes, the versatility and plasticity of RNA molecules, together with their high flexibility and dynamism, determines formation of macromolecular complexes in response to different signals. These properties rely on the presence of short RNA motifs, which operate as modular entities, and suggest that decomposition of IRES elements in short modules could help to understand the different mechanisms driven by these regulatory elements. Here we will review evidence suggesting that model IRES elements consist of the combination of short modules, providing sites of interaction for ribosome subunits, eIFs and RBPs, with implications for definition of criteria to identify novel IRES-like elements genome wide.

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