Post-transcriptional regulation of Pabpn1 by the RNA binding protein HuR

Phillips, Brittany L.; Banerjee, Ayan; Sánchez, Brenda Janice; Marco, Sergio Di; Gallouzi, Imed Eddine; Pavlath, Grace K.; Corbett, Anita H.

doi:10.1093/nar/gky535

Cited by 13 publications

(17 citation statements)

References 85 publications

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“…Consistent with previous observations 26 , we were unsuccessful in immunoprecipitating HuR from skeletal muscle extracts. Therefore, we used the well-established C2C12 myoblasts, to assess, as we did before 9,11,12,27 , the association between HuR and PGC-1α mRNA. Similar to what was observed in the soleus , small- interfering ribonucleic acid (siRNA)-mediated HuR depletion in C2C12 myoblasts 11,12 significantly increased PGC-1α mRNA and protein levels (Fig.…”

Section: Resultsmentioning

confidence: 99%

Depletion of HuR in murine skeletal muscle enhances exercise endurance and prevents cancer-induced muscle atrophy

et al. 2019

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The master posttranscriptional regulator HuR promotes muscle fiber formation in cultured muscle cells. However, its impact on muscle physiology and function in vivo is still unclear. Here, we show that muscle-specific HuR knockout (muHuR-KO) mice have high exercise endurance that is associated with enhanced oxygen consumption and carbon dioxide production. muHuR-KO mice exhibit a significant increase in the proportion of oxidative type I fibers in several skeletal muscles. HuR mediates these effects by collaborating with the mRNA decay factor KSRP to destabilize the PGC-1α mRNA. The type I fiber-enriched phenotype of muHuR-KO mice protects against cancer cachexia-induced muscle loss. Therefore, our study uncovers that under normal conditions HuR modulates muscle fiber type specification by promoting the formation of glycolytic type II fibers. We also provide a proof-of-principle that HuR expression can be targeted therapeutically in skeletal muscles to combat cancer-induced muscle wasting.

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Section: Resultsmentioning

confidence: 99%

Depletion of HuR in murine skeletal muscle enhances exercise endurance and prevents cancer-induced muscle atrophy

et al. 2019

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“…In fact, recent studies suggest that the pathogenic mechanism of OPMD is related to sequestration of PABPN1, other proteins, and RNAs in nuclear aggregates, thus decreasing the functional pools of these important molecules (7,13,14). Given that PABPN1 protein levels in muscle are already low (15), sequestration into aggregates or interaction with alanine-expanded PABPN1 may decrease available PABPN1 below some threshold required for normal muscle function (15,16). If alanine expansion also impairs normal PABPN1 function, this could compound any defects associated with decreased PABPN1 availability and exacerbate pathology.…”

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confidence: 99%

Proteomic analysis reveals that wildtype and alanine-expanded nuclear poly(A)-binding protein exhibit differential interactions in skeletal muscle

Banerjee

Phillips

Deng

et al. 2019

Journal of Biological Chemistry

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Oculopharyngeal muscular dystrophy (OPMD) is a late-onset, primarily autosomal dominant disease caused by a short GCN expansion in the PABPN1 (polyadenylate-binding protein nuclear 1) gene that results in an alanine expansion at the N terminus of the PABPN1 protein. Expression of alanine-expanded PABPN1 is linked to the formation of nuclear aggregates in tissues from individuals with OPMD. However, as with other nuclear aggregate-associated diseases, controversy exists over whether these aggregates are the direct cause of pathology. An emerging hypothesis is that a loss of PABPN1 function and/or aberrant protein interactions contribute to pathology in OPMD. Here, we present the first global proteomic analysis of the protein interactions of WT and alanine-expanded PABPN1 in skeletal muscle tissue. These data provide both insight into the function of PABPN1 in muscle and evidence that the alanine expansion alters the protein-protein interactions of PABPN1. We extended this analysis to demonstrate altered complex formation with and loss of function of TDP-43 (TAR DNA-binding protein 43), which we show interacts with alanine-expanded but not WT PABPN1. The results from our study support a model where altered protein interactions with alanine-expanded PABPN1 that lead to loss or gain of function could contribute to pathology in OPMD.

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“…Further analyses showed that the human antigen R (HuR) protein interacts with ARE4 and represses Pabpn1 expression in mature muscle. [91] The two isoforms of Pabpn1 also trigger PABPN1 autoregulation. The distal PAS creates an unspliced pre-mRNA that includes intron 6.…”

Section: The Regulation Of Pabpnsmentioning

confidence: 99%

“…Further analyses showed that the human antigen R (HuR) protein interacts with ARE4 and represses Pabpn1 expression in mature muscle. [ 91 ]…”

Section: Nuclear Poly(a) Binding Proteinsmentioning

confidence: 99%

Revisiting poly(A)‐binding proteins: Multifaceted regulators during gametogenesis and early embryogenesis

Zhao

Fan

2021

BioEssays

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Post-transcriptional regulation faces a distinctive challenge in gametes. Transcription is limited when the germ cells enter the division phase due to condensed chromatin, while gene expression during gamete maturation, fertilization, and early cleavage depends on existing mRNA post-transcriptional coordination. The dynamics of the 3ʹ-poly(A) tail play crucial roles in defining mRNA fate. The 3ʹ-poly(A) tail is covered with poly(A)-binding proteins (PABPs) that help to mediate mRNA metabolism and recent work has shed light on the number and function of germ cell-specific expressed PABPs. There are two structurally different PABP groups distinguished by their cytoplasmic and nuclear localization. Both lack catalytic activity but are coupled with various roles through their interaction with multifunctional partners during mRNA metabolism. Here, we present a synopsis of PABP function during gametogenesis and early embryogenesis and describe both conventional and current models of the functions and regulation of PABPs, with an emphasis on the physiological significance of how germ cell-specific PABPs potentially affect human fertility.

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Post-transcriptional regulation of Pabpn1 by the RNA binding protein HuR

Cited by 13 publications

References 85 publications

Depletion of HuR in murine skeletal muscle enhances exercise endurance and prevents cancer-induced muscle atrophy

Depletion of HuR in murine skeletal muscle enhances exercise endurance and prevents cancer-induced muscle atrophy

Proteomic analysis reveals that wildtype and alanine-expanded nuclear poly(A)-binding protein exhibit differential interactions in skeletal muscle

Revisiting poly(A)‐binding proteins: Multifaceted regulators during gametogenesis and early embryogenesis

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