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Alternative splicing of P2RX7 pre-messenger RNA in health and diseases: Myth or reality?

ABSTRACT: Alternative splicing (AS) tremendously increases the use of genetic information by generating protein isoforms that differ in protein-protein interactions, catalytic activity and/or subcellular localization. This review is not dedicated to AS in general, but rather we focus our attention on AS of P2RX7 pre-mRNA. Whereas P2RX7 mRNA is expressed by virtually all eukaryotic mammalian cells, the expression of this channel receptor is restrained to certain cells. When expressed at the cell membrane, P2RX7 controls downstream events including release of inflammatory molecules, phagocytosis, cell proliferation and death and metabolic events. Therefore, P2RX7 is an important actor of health and diseases. In this review, we summarize the general mechanisms leading to AS. Further, we recapitulate our current knowledge concerning the functional regions in P2RX7, identified at the genetic or exonic levels, and how AS may affect the expression of these regions. Finally, the potential of P2RX7 splice variants to control the fate of cancer cells is discussed.

SUBMITTER: Benzaquen J

PROVIDER: S-EPMC6717933 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Alternative splicing of P2RX7 pre-messenger RNA in health and diseases: Myth or reality?

Benzaquen Jonathan J Heeke Simon S Janho Dit Hreich Séréna S Douguet Laetitia L Marquette Charles Hugo CH Hofman Paul P Vouret-Craviari Valérie V

Biomedical journal 20190601 3

Alternative splicing (AS) tremendously increases the use of genetic information by generating protein isoforms that differ in protein-protein interactions, catalytic activity and/or subcellular localization. This review is not dedicated to AS in general, but rather we focus our attention on AS of P2RX7 pre-mRNA. Whereas P2RX7 mRNA is expressed by virtually all eukaryotic mammalian cells, the expression of this channel receptor is restrained to certain cells. When expressed at the cell membrane, ...[more]

PMID: 31466708

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Project description:ObjectiveScleroderma (systemic sclerosis [SSc]) is a complex connective tissue disorder characterized by hardening and thickening of the skin. One hallmark of scleroderma is excessive accumulation of collagen accompanied by increased levels of pyridinoline collagen crosslinks derived from hydroxylysine residues in the collagen telopeptide domains. Lysyl hydroxylase 2 (LH2), an important alternatively spliced enzyme in collagen biosynthesis, acts as a collagen telopeptide hydroxylase. Changes in the pattern of LH2 alternative splicing, favoring increased inclusion of the alternatively spliced LH2 exon 13A, thereby increasing the levels of the long transcript of LH2 (LH2[long]), are linked to scleroderma disease. This study was undertaken to examine the role played by RNA binding protein Fox-2 in regulating exon 13A inclusion, which leads to the generation of scleroderma-associated LH2(long) messenger RNA (mRNA).MethodsPhylogenetic sequence analysis of introns flanking exon 13A was performed. A tetracycline-inducible system in T-Rex 293 cells was used to induce Fox-2 protein, and endogenous LH2(long) mRNA was determined by reverse transcriptase-polymerase chain reaction. An LH2 minigene was designed, validated, and used in Fox-2 overexpression and mutagenesis experiments. Knockdown of Fox-2 was performed in mouse embryonic fibroblasts and in fibroblasts from SSc patients.ResultsOverexpression of Fox-2 enhanced the inclusion of exon 13A and increased the generation of LH2(long) mRNA, whereas knockdown of Fox-2 decreased LH2(long) transcripts. Mutational analysis of an LH2 minigene demonstrated that 2 of the 4 Fox binding motifs flanking LH2 exon 13A are required for inclusion of exon 13A. In early passage fibroblasts derived from patients with scleroderma, the knockdown of Fox-2 protein significantly decreased the endogenous levels of LH2(long) mRNA.ConclusionOur findings indicate that Fox-2 plays an integral role in the regulation of LH2 splicing. Knockdown of Fox-2 and other methods to decrease the levels of fibrosis-associated LH2(long) mRNA in primary scleroderma cells may suggest a novel approach to strategies directed against scleroderma.

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Alternative splicing of P2RX7 pre-messenger RNA in health and diseases: Myth or reality?

Publications

Alternative splicing of P2RX7 pre-messenger RNA in health and diseases: Myth or reality?

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