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Heterogeneous nuclear ribonucleoprotein A1 interacts with microRNA-34a to promote chondrogenic differentiation of mesenchymal stem cells.

ABSTRACT: The mesenchymal stem cell (MSC) shows potential in degenerative disc disease (DDD) treatment. However, little is known about the function of heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) in modulating the chondrogenic differentiation of MSCs. This study aimed to investigate the role of hnRNPA1 in the chondrogenic differentiation of MSCs and potential mechanisms. Mouse MSCs C3H10 and chondrogenic ATDC5 cells were used to quantify hnRNPA1 expression. The hnRNPA1 overexpression vectors were transfected into C3H10 cells, cell viability and chondrogenic factors expressions were assessed by MTT assay, qPCR and Western blot, respectively. After microRNA-34a (miR-34a) inhibitor transfection, expressions of chondrogenic factors and the Wnt signaling were detected. RNA-binding protein immunoprecipitation (RIP) was performed to reveal the interaction between hnRNPA1 and miR-34a. Results showed that hnRNPA1 was significantly down-regulated in C3H10 compared to ATDC5.Overexpression of hnRNPA1 markedly promoted C3H10 cell viability and expressions of chondrogenic factors SRY-box 9 (SOX9), collagen II, hyaluronan synthase 2 (HAS2) and aggrecan, without significant influence on adipogenic factors. miR-34a inhibitor suppressed chondrogenic factors expressions. RIP results showed the interaction between miR-34a and hnRNPA1. Besides, hnRNPA1 promoted expressions of Wnt family member 3A (WNT3A), WNT5A and ?-catenin, and these effects were abrogated by miR-34a inhibitor. We fund the promotive effect of hnRNPA1 on chondrogenic factors, which might require the interaction with miR-34a and the regulation of the Wnt signaling. Thus hnRNPA1 might induce the chondrogenic differentiation of MSCs that facilitate the MSC therapy for DDD.

SUBMITTER: Meng X

PROVIDER: S-EPMC5411925 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Heterogeneous nuclear ribonucleoprotein A1 interacts with microRNA-34a to promote chondrogenic differentiation of mesenchymal stem cells.

Meng Xianglong X Cui Jiawen J Wang Yunsheng Y Zhang Xinuo X Li Dongyue D Hai Yong Y Du Hongwu H

American journal of translational research 20170415 4

The mesenchymal stem cell (MSC) shows potential in degenerative disc disease (DDD) treatment. However, little is known about the function of heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) in modulating the chondrogenic differentiation of MSCs. This study aimed to investigate the role of hnRNPA1 in the chondrogenic differentiation of MSCs and potential mechanisms. Mouse MSCs C3H10 and chondrogenic ATDC5 cells were used to quantify hnRNPA1 expression. The hnRNPA1 overexpression vectors were ...[more]

PMID: 28469782

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Project description:Avian reovirus (ARV) p17 protein continuously shuttles between the nucleus and the cytoplasm via transcription-dependent and chromosome region maintenance 1 (CRM1)-independent mechanisms. Nevertheless, whether cellular proteins modulate nucleocytoplasmic shuttling of p17 remains unknown. This is the first report that heterogeneous nuclear ribonucleoprotein (hnRNP) A1 serves as a carrier protein to modulate nucleocytoplasmic shuttling of p17. Both in vitro and in vivo studies indicated that direct interaction of p17 with hnRNP A1 maps within the amino terminus (amino acids [aa] 19 to 40) of p17 and the Gly-rich region of the C terminus of hnRNP A1. Furthermore, our results reveal that the formation of p17-hnRNP A1-transportin 1 carrier-cargo complex is required to modulate p17 nuclear import. Utilizing sequence and mutagenesis analyses, we have identified nuclear export signal (NES) 19LSLRELAI26 of p17. Mutations of these residues causes a nuclear retention of p17. In this work, we uncovered that the N-terminal 21 amino acids (aa 19 to 40) of p17 that comprise the NES can modulate both p17 and hnRNP A1 interaction and nucleocytoplasmic shuttling of p17. In this work, the interaction site of p17 with lamin A/C was mapped within the amino terminus (aa 41 to 60) of p17 and p17 colocalized with lamin A/C at the nuclear envelope. Knockdown of hnRNP A1 or lamin A/C led to inhibition of nucleocytoplasmic shuttling of p17 and reduced virus yield. Collectively, the results of this study provide mechanistic insights into hnRNP A1 and lamin A/C-modulated nucleocytoplasmic shuttling of the ARV p17 protein.IMPORTANCE Avian reoviruses (ARVs) cause considerable economic losses in the poultry industry. The ARV p17 protein continuously shuttles between the nucleus and the cytoplasm to regulate several cellular signaling pathways and interacts with several cellular proteins to cause translation shutoff, cell cycle arrest, and autophagosome formation, all of which enhance virus replication. To date the mechanisms underlying nucleocytoplasmic shuttling of p17 remain largely unknown. Here we report that hnRNP A1 and lamin A/C serve as carrier and mediator proteins to modulate nucleocytoplasmic shuttling of p17. The formation of p17-hnRNP A1-transportin 1 carrier-cargo complex is required to modulate p17 nuclear import. Furthermore, we have identified an NES-containing nucleocytoplasmic shuttling domain (aa 19 to 40) of p17 that is critical for binding to hnRNP A1 and for nucleocytoplasmic shuttling of p17. This study provides novel insights into how hnRNP A1 and lamin A/C modulate nucleocytoplasmic shuttling of the ARV p17 protein.

Dataset Information

Heterogeneous nuclear ribonucleoprotein A1 interacts with microRNA-34a to promote chondrogenic differentiation of mesenchymal stem cells.

Publications

Heterogeneous nuclear ribonucleoprotein A1 interacts with microRNA-34a to promote chondrogenic differentiation of mesenchymal stem cells.

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