Activation of p38 signaling increases utrophin A expression in skeletal muscle via the RNA-binding protein KSRP and inhibition of AU-rich element-mediated mRNA decay: implications for novel DMD therapeutics

Innervation of skeletal muscle by motor neurons occurs through the neuromuscular junction, a cholinergic synapse essential for normal muscle growth and function. Defects in nerve–muscle signaling cause a variety of neuromuscular disorders with features of ataxia, paralysis, skeletal muscle wasting, and degeneration. Here we show that the nuclear zinc finger protein ZFP106 is highly enriched in skeletal muscle and is required for postnatal maintenance of myofiber innervation by motor neurons. Genetic disruption of Zfp106 in mice results in progressive ataxia and hindlimb paralysis associated with motor neuron degeneration, severe muscle wasting, and premature death by 6 mo of age. We show that ZFP106 is an RNA-binding protein that associates with the core splicing factor RNA binding motif protein 39 (RBM39) and localizes to nuclear speckles adjacent to spliceosomes. Upon inhibition of pre-mRNA synthesis, ZFP106 translocates with other splicing factors to the nucleolus. Muscle and spinal cord of Zfp106 knockout mice displayed a gene expression signature of neuromuscular degeneration. Strikingly, altered splicing of the Nogo (Rtn4) gene locus in skeletal muscle of Zfp106 knockout mice resulted in ectopic expression of NOGO-A, the neurite outgrowth factor that inhibits nerve regeneration and destabilizes neuromuscular junctions. These findings reveal a central role for Zfp106 in the maintenance of nerve–muscle signaling, and highlight the involvement of aberrant RNA processing in neuromuscular disease pathogenesis.

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The RNA binding protein HuR influences skeletal muscle metabolic flexibility in rodents and humans

Metabolism ◽

10.1016/j.metabol.2019.05.010 ◽

2019 ◽

Vol 97 ◽

pp. 40-49 ◽

Cited By ~ 5

Author(s):

Randall L. Mynatt ◽

Robert C. Noland ◽

Carrie M. Elks ◽

Bolormaa Vandanmagsar ◽

David S. Bayless ◽

...

Keyword(s):

Skeletal Muscle ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Metabolic Flexibility

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Converging pathways involving microRNA-206 and the RNA-binding protein KSRP control post-transcriptionally utrophin A expression in skeletal muscle

Nucleic Acids Research ◽

10.1093/nar/gkt1350 ◽

2013 ◽

Vol 42 (6) ◽

pp. 3982-3997 ◽

Cited By ~ 17

Author(s):

Adel Amirouche ◽

Helina Tadesse ◽

Pedro Miura ◽

Guy Bélanger ◽

John A. Lunde ◽

...

Keyword(s):

Skeletal Muscle ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Control Post

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The RNA-binding protein Staufen1 is increased in DM1 skeletal muscle and promotes alternative pre-mRNA splicing

The Journal of Cell Biology ◽

10.1083/jcb.201108113 ◽

2012 ◽

Vol 196 (6) ◽

pp. 699-712 ◽

Cited By ~ 72

Author(s):

Aymeric Ravel-Chapuis ◽

Guy Bélanger ◽

Ramesh S. Yadava ◽

Mani S. Mahadevan ◽

Luc DesGroseillers ◽

...

Keyword(s):

Skeletal Muscle ◽

Alternative Splicing ◽

Nuclear Export ◽

Rna Binding ◽

Rna Binding Proteins ◽

Binding Protein ◽

Rna Binding Protein ◽

Splicing Regulation ◽

Ribonucleic Acids ◽

Dystrophia Myotonica Protein Kinase

In myotonic dystrophy type 1 (DM1), dystrophia myotonica protein kinase messenger ribonucleic acids (RNAs; mRNAs) with expanded CUG repeats (CUGexp) aggregate in the nucleus and become toxic to cells by sequestering and/or misregulating RNA-binding proteins, resulting in aberrant alternative splicing. In this paper, we find that the RNA-binding protein Staufen1 is markedly and specifically increased in skeletal muscle from DM1 mouse models and patients. We show that Staufen1 interacts with mutant CUGexp mRNAs and promotes their nuclear export and translation. This effect is critically dependent on the third double-stranded RNA–binding domain of Staufen1 and shuttling of Staufen1 into the nucleus via its nuclear localization signal. Moreover, we uncover a new role of Staufen1 in splicing regulation. Overexpression of Staufen1 rescues alternative splicing of two key pre-mRNAs known to be aberrantly spliced in DM1, suggesting its increased expression represents an adaptive response to the pathology. Altogether, our results unravel a novel function for Staufen1 in splicing regulation and indicate that it may positively modulate the complex DM1 phenotype, thereby revealing its potential as a therapeutic target.

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The RNA Binding Protein ELF9 Directly Reduces SUPPRESSOR OF OVEREXPRESSION OF CO1 Transcript Levels in Arabidopsis, Possibly via Nonsense-Mediated mRNA Decay

The Plant Cell ◽

10.1105/tpc.108.064774 ◽

2009 ◽

Vol 21 (4) ◽

pp. 1195-1211 ◽

Cited By ~ 17

Author(s):

Hae-Ryong Song ◽

Ju-Dong Song ◽

Jung-Nam Cho ◽

Richard M. Amasino ◽

Bosl Noh ◽

...

Keyword(s):

Mrna Decay ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Transcript Levels ◽

Nonsense Mediated Mrna Decay

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Picornavirus Modification of a Host mRNA Decay Protein

mBio ◽

10.1128/mbio.00431-12 ◽

2012 ◽

Vol 3 (6) ◽

Cited By ~ 41

Author(s):

Janet M. Rozovics ◽

Amanda J. Chase ◽

Andrea L. Cathcart ◽

Wayne Chou ◽

Paul D. Gershon ◽

...

Keyword(s):

Host Cell ◽

Mrna Decay ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Binding Protein ◽

Rna Binding Protein ◽

Rna Replication ◽

Human Rhinovirus ◽

Genomic Rnas

ABSTRACTDue to the limited coding capacity of picornavirus genomic RNAs, host RNA binding proteins play essential roles during viral translation and RNA replication. Here we describe experiments suggesting that AUF1, a host RNA binding protein involved in mRNA decay, plays a role in the infectious cycle of picornaviruses such as poliovirus and human rhinovirus. We observed cleavage of AUF1 during poliovirus or human rhinovirus infection, as well as interaction of this protein with the 5′ noncoding regions of these viral genomes. Additionally, the picornavirus proteinase 3CD, encoded by poliovirus or human rhinovirus genomic RNAs, was shown to cleave all four isoforms of recombinant AUF1 at a specific N-terminal sitein vitro. Finally, endogenous AUF1 was found to relocalize from the nucleus to the cytoplasm in poliovirus-infected HeLa cells to sites adjacent to (but distinct from) putative viral RNA replication complexes.IMPORTANCEThis study derives its significance from reporting how picornaviruses like poliovirus and human rhinovirus proteolytically cleave a key player (AUF1) in host mRNA decay pathways during viral infection. Beyond cleavage of AUF1 by the major viral proteinase encoded in picornavirus genomes, infection by poliovirus results in the relocalization of this host cell RNA binding protein from the nucleus to the cytoplasm. The alteration of both the physical state of AUF1 and its cellular location illuminates how small RNA viruses manipulate the activities of host cell RNA binding proteins to ensure a faithful intracellular replication cycle.

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Loss of RNA-Binding Protein Sfpq Causes Long-Gene Transcriptopathy in Skeletal Muscle and Severe Muscle Mass Reduction with Metabolic Myopathy

iScience ◽

10.1016/j.isci.2019.02.023 ◽

2019 ◽

Vol 13 ◽

pp. 229-242 ◽

Cited By ~ 6

Author(s):

Motoyasu Hosokawa ◽

Akihide Takeuchi ◽

Jun Tanihata ◽

Kei Iida ◽

Shin'ichi Takeda ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Metabolic Myopathy ◽

Mass Reduction

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Fragile X-Related Protein 1 (FXR1) Promotes Trophoblast Migration at Early Pregnancy via Downregulation of GDF-15 Expression

Reproductive Sciences ◽

10.1007/s43032-021-00693-1 ◽

2021 ◽

Author(s):

Wei Hong ◽

Jin-Hong Chen ◽

Hong-jiao Ma ◽

Li-Li ◽

Xiao-Cui Li

Keyword(s):

Mrna Decay ◽

Rna Binding ◽

Ex Vivo ◽

Fragile X ◽

Binding Protein ◽

Rna Binding Protein ◽

Explant Culture ◽

Extravillous Trophoblast ◽

Related Protein ◽

Trophoblast Migration

AbstractFragile X-related protein 1 (FXR1) is an RNA-binding protein that can regulate specific mRNA decay in cells. Our previous study showed that FXR1 expression was significantly decreased in trophoblasts from patients with unexplained recurrent spontaneous abortion (RSA); however, the role of FXR1 in trophoblast function during early placenta development has not been fully elucidated. In this study, we found that knockdown of FXR1 using siRNA effectively inhibited the migration of HTR-8 cells and extravillous trophoblast (EVT) outgrowth in an ex vivo extravillous explant culture model. Furthermore, through analysis of a panel of cytokines, we found that the GDF-15 protein was upregulated after knockdown of FXR1 in HTR-8/SVneo cells. This was further confirmed by western blotting and immunofluorescence in HTR-8/SVneo cells and an extravillous explant. Our data also showed that FXR1 expression was downregulated and GDF-15 was upregulated in chorionic villous tissues from RSA patients compared with those from healthy controls (HCs). Further, immunohistochemistry showed a strong expression of GDF-15 in chorionic villous tissue in the RSA group, which was mainly distributed in villous trophoblasts (CTBs) and syncytiotrophoblasts (STBs). Moreover, knockdown of GDF-15 enhanced the migration of HTR-8 cells, while overexpression of GDF-15 using plasmid or treatment with recombinant human GDF-15 protein inhibited trophoblast migration. Importantly, RNA-binding protein immunoprecipitation showed that FXR1 directly bound to the 3′-UTR of GDF-15 mRNA to promote GDF-15 mRNA decay. Together, our data provide new insight into the function of FXR1 in human placenta via regulation of GDF-15 expression in trophoblasts and suggest a possible pathological process involved in RSA.

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