Organ-specific PTB1-associated microRNAs determine expression of pyruvate kinase isoforms

Taniguchi, Kohei; Ito, Yuko; Sugito, Nobuhiko; Kumazaki, Minami; Shinohara, Haruka; Yamada, Nami; Nakagawa, Yoshihito; Sugiyama, Tarou; Futamura, Manabu; Otsuki, Yoshinori; Yoshida, Kazuhiro; Uchiyama, Kazuhisa; Akao, Yukihiro

doi:10.1038/srep08647

Cited by 50 publications

(70 citation statements)

References 42 publications

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“…In contrast, the V4 (and also V1) isoforms are not detected in unstimulated T cells (59). In addition, cell-type specific post-transcriptional regulation, for example by the expression of cell-specific microRNAs, may be involved in differences in IRF5 expression (60, 61). Basal IRF5 expression among pDCs is heterogeneous with some pDCs expressing no or low levels of IRF5.…”

Section: Discussionmentioning

confidence: 99%

Sex Differences in Plasmacytoid Dendritic Cell Levels of IRF5 Drive Higher IFN-α Production in Women

Griesbeck

Ziegler

Laffont

et al. 2015

The Journal of Immunology

201

160

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Increased IFNα production contributes to the pathogenesis of infectious and autoimmune diseases. Plasmacytoid dendritic cells (pDCs) from females produce more IFNα upon TLR7 stimulation than pDCs from males, yet the mechanisms underlying this difference remain unclear. Here, we show that basal levels of interferon regulatory factor 5 (IRF5) in pDCs were significantly higher in females compared to males and positively correlated with the percentage of IFNα-secreting pDCs. Delivery of recombinant IRF5 protein into human primary pDCs increased TLR7-mediated IFNα secretion. In mice, genetic ablation of the estrogen receptor 1 (Esr1) gene in the hematopoietic compartment or DC lineage reduced IRF5 mRNA expression in pDCs and IFNα production. IRF5 mRNA levels furthermore correlated with Esr1 mRNA levels in human pDCs, consistent with IRF5 regulation at the transcriptional level by Esr1. Taken together, these data demonstrate a critical mechanism by which sex differences in basal pDC IRF5 expression lead to higher IFNα production upon TLR7 stimulation in females, and provide novel targets for the modulation of immune responses and inflammation.

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Section: Discussionmentioning

confidence: 99%

Sex Differences in Plasmacytoid Dendritic Cell Levels of IRF5 Drive Higher IFN-α Production in Women

Griesbeck

Ziegler

Laffont

et al. 2015

The Journal of Immunology

201

160

View full text Add to dashboard Cite

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“…PKM1 is expressed in energy-consuming tissues, including brain and skeletal muscle, whereas PKM2 is expressed more dominantly in embryonic cells (19). We previously observed a change in expression of Pkm isoforms, i.e., from Pkm2 to Pkm1, during neuronal differentiation of mouse embryonal carcinoma P19 cells (1).…”

Section: Resultsmentioning

confidence: 99%

“…PKM2 contributes to intricate metabolic reprogramming via the monomer-dimertetramer interconversion, and it also can transcriptionally modulate gene expression (18). In contrast, PKM1 essentially promotes OXPHOS in energy-consuming tissues, such as brain and muscle (19). The PKM isoform switch correlates with metabolic changes during myoblast differentiation into myotubes (20).…”

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confidence: 99%

RBM4 Regulates Neuronal Differentiation of Mesenchymal Stem Cells by Modulating Alternative Splicing of Pyruvate Kinase M

Hung

et al. 2017

Molecular and Cellular Biology

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RBM4 promotes differentiation of neuronal progenitor cells and neurite outgrowth of cultured neurons via its role in splicing regulation. In this study, we further explored the role of RBM4 in neuronal differentiation. During neuronal differentiation, energy production shifts from glycolysis to oxidative phosphorylation. We found that the splice isoform change of the metabolic enzyme pyruvate kinase M (PKM) from PKM2 to PKM1 occurs during brain development and is impaired in RBM4-deficient brains. The PKM isoform change could be recapitulated in human mesenchymal stem cells (MSCs) during neuronal induction. Using a PKM minigene, we demonstrated that RBM4 plays a direct role in regulating alternative splicing of PKM. Moreover, RBM4 antagonized the function of the splicing factor PTB and induced the expression of a PTB isoform with attenuated splicing activity in MSCs. Overexpression of RBM4 or PKM1 induced the expression of neuronal genes, increased the mitochondrial respiration capacity in MSCs, and, accordingly, promoted neuronal differentiation. Finally, we demonstrated that RBM4 is induced and is involved in the PKM splicing switch and neuronal gene expression during hypoxiainduced neuronal differentiation. Hence, RBM4 plays an important role in the PKM isoform switch and the change in mitochondrial energy production during neuronal differentiation.KEYWORDS alternative splicing, hypoxia, mesenchymal stem cells, neuronal differentiation, pyruvate kinase M T he splicing regulator RBM4 modulates alternative splicing of a number of transcripts involved in cell differentiation and tumorigenesis (1, 2). Previous studies demonstrated the role of RBM4 in differentiation of muscle and pancreas cells and adipocytes (3-5). We recently reported that RBM4 is also involved in neuronal differentiation of mouse embryonal carcinoma P19 cells and neural progenitor-derived cells (1). RBM4 promotes the expression of Numb splice isoforms that function during neuronal differentiation as well as neurite outgrowth. Mesenchymal stem cells (MSCs) are adult bone marrow stromal cells that can differentiate into a variety of cell types, including neurons, and have potential in regenerative therapy for neurological diseases (6). In this study, we assessed whether RBM4 can also modulate neuronal differentiation of MSCs and explored the underlying mechanism.Cellular energy metabolism undergoes a dynamic change during development. In principle, anabolic glycolysis dominates in embryonic stem cells and permits rapid cell proliferation similar to that in cancer cells (7,8). Most adult stem cells exhibit low glycolysis activity in a quiescent state and undertake active glycolysis while proliferat-

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“…Thus, it is also possible that hnRNPI may regulate the expression of proteins that alter IRAK1 protein turnover. Of note, hnRNPI is capable of modulating the activity of microRNAs in disease pathogenesis and many important biological processes [30,39–42]. It has been reported that miR-146a controls both translation and degradation of epithelial IRAK1 in the neonatal intestine [19].…”

Section: Discussionmentioning

confidence: 99%

hnRNP I regulates neonatal immune adaptation and prevents colitis and colorectal cancer

et al. 2017

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The intestinal epithelium plays a critical role in host-microbe homeostasis by sensing gut microbes and subsequently initiating proper immune responses. During the neonatal stage, the intestinal epithelium is under immune repression, allowing the transition for newborns from a relatively sterile intra-uterine environment to one that is rich in foreign antigens. The mechanism underlying such immune repression remains largely unclear, but involves downregulation of IRAK1 (interleukin-1 receptor-associated kinase), an essential component of toll-like receptor-mediated NF-κB signaling. We report here that heterogeneous nuclear ribonucleoprotein I (hnRNPI), an RNA binding protein, is essential for regulating neonatal immune adaptation. We generated a mouse model in which hnRNPI is ablated specifically in the intestinal epithelial cells, and characterized intestinal defects in the knockout mice. We found that loss of hnRNPI function in mouse intestinal epithelial cells results in early onset of spontaneous colitis followed by development of invasive colorectal cancer. Strikingly, the epithelium-specific hnRNPI knockout neonates contain aberrantly high IRAK1 protein levels in the colons and fail to develop immune tolerance to environmental microbes. Our results demonstrate that hnRNPI plays a critical role in establishing neonatal immune adaptation and preventing colitis and colorectal cancer.

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Organ-specific PTB1-associated microRNAs determine expression of pyruvate kinase isoforms

Cited by 50 publications

References 42 publications

Sex Differences in Plasmacytoid Dendritic Cell Levels of IRF5 Drive Higher IFN-α Production in Women

Sex Differences in Plasmacytoid Dendritic Cell Levels of IRF5 Drive Higher IFN-α Production in Women

RBM4 Regulates Neuronal Differentiation of Mesenchymal Stem Cells by Modulating Alternative Splicing of Pyruvate Kinase M

hnRNP I regulates neonatal immune adaptation and prevents colitis and colorectal cancer

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