Zinc‐induced modulation of <scp>SRSF</scp>6 activity alters Bim splicing to promote generation of the most potent apoptotic isoform BimS

Hara, Hirokazu; Takeda, Tatsuya; Yamamoto, Nozomi; Furuya, Keisuke; Hirose, Kazuya; Kamiya, Tetsuro; Adachi, Tetsuo

doi:10.1111/febs.12318

Cited by 21 publications

(22 citation statements)

References 46 publications

(61 reference statements)

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“…Bim undergoes alternative splicing to produce three splicing variants (Bim EL , Bim L and Bim S ). The smallest variant Bim S is the most potent inducer of apoptosis [33]. Interestingly, Bim S isoform was upregualated by EP3 dependent PGE 2 activation as well as by cytokine withdrawal.…”

Section: Discussionmentioning

confidence: 97%

PGE2 Promotes Apoptosis Induced by Cytokine Deprivation through EP3 Receptor and Induces Bim in Mouse Mast Cells

Kovářová

Koller

2014

PLoS ONE

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Increased mast cell numbers are observed at sites of allergic inflammation and restoration of normal mast cell numbers is critical to the resolution of these responses. Early studies showed that cytokines protect mast cells from apoptosis, suggesting a simple model in which diminished cytokine levels during resolution leads to cell death. The report that prostaglandins can contribute both to recruitment and to the resolution of inflammation together with the demonstration that mast cells express all four PGE2 receptors raises the question of whether a single PGE2 receptor mediates the ability of PGE2 to regulate mast cell survival and apoptosis. We report here that PGE2 through the EP3 receptor promotes cell death of mast cells initiated by cytokine withdrawal. Furthermore, the ability of PGE2 to limit reconstitution of tissues with cultured mast cells is lost in cell lacking the EP3 receptor. Apoptosis is accompanied by higher dissipation of mitochondrial potential (ΔΨm), increased caspase-3 activation, chromatin condensation, and low molecular weight DNA cleavage. PGE2 augmented cell death is dependent on an increase in intracellular calcium release, calmodulin dependent kinase II and MAPK activation. Synergy between the EP3 pathway and the intrinsic mitochondrial apoptotic pathway results in increased Bim expression and higher sensitivity of mast cells to cytokine deprivation. This supports a model in which PGE2 can contribute to the resolution of inflammation in part by augmenting the removal of inflammatory cells in this case, mast cells.

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Section: Discussionmentioning

confidence: 97%

PGE2 Promotes Apoptosis Induced by Cytokine Deprivation through EP3 Receptor and Induces Bim in Mouse Mast Cells

Kovářová

Koller

2014

PLoS ONE

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“…Despite numerous reports that abiotic stress markedly affects plant mRNA splicing, virtually nothing is known about the effects of metal ions. Interestingly, in humans Zn has been shown to modulate alternative splicing of the hypoxia-inducible factor HIF1 [53] and the pro-apoptotic Bim [54] genes.…”

Section: Discussionmentioning

confidence: 99%

Intron Retention in the 5′UTR of the Novel ZIF2 Transporter Enhances Translation to Promote Zinc Tolerance in Arabidopsis

et al. 2014

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Root vacuolar sequestration is one of the best-conserved plant strategies to cope with heavy metal toxicity. Here we report that zinc (Zn) tolerance in Arabidopsis requires the action of a novel Major Facilitator Superfamily (MFS) transporter. We show that ZIF2 (Zinc-Induced Facilitator 2) localises primarily at the tonoplast of root cortical cells and is a functional transporter able to mediate Zn efflux when heterologously expressed in yeast. By affecting plant tissue partitioning of the metal ion, loss of ZIF2 function exacerbates plant sensitivity to excess Zn, while its overexpression enhances Zn tolerance. The ZIF2 gene is Zn-induced and an intron retention event in its 5′UTR generates two splice variants (ZIF2.1 and ZIF2.2) encoding the same protein. Importantly, high Zn favours production of the longer ZIF2.2 transcript, which compared to ZIF2.1 confers greater Zn tolerance to transgenic plants by promoting higher root Zn immobilization. We show that the retained intron in the ZIF2 5′UTR enhances translation in a Zn-responsive manner, markedly promoting ZIF2 protein expression under excess Zn. Moreover, Zn regulation of translation driven by the ZIF2.2 5′UTR depends largely on a predicted stable stem loop immediately upstream of the start codon that is lost in the ZIF2.1 5′UTR. Collectively, our findings indicate that alternative splicing controls the levels of a Zn-responsive mRNA variant of the ZIF2 transporter to enhance plant tolerance to the metal ion.

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“…Bim S is not subject to any known post-translational regulation, being the most potent apoptosis inducer among the three isoforms. SRp55 promotes the inclusion of exon 4 through binding to a predicted ISE located in intron 4 (126). Thus, decreased expression of SRp55 leads to increased Bim S expression and consequent augmented apoptosis.…”

Section: Figurementioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Alternative splicing: the new frontier in diabetes research

Juan-Mateu

Villate

Eizirik

2016

European Journal of Endocrinology

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Type 1 diabetes (T1D) is a chronic autoimmune disease in which pancreatic β cells are killed by infiltrating immune cells and by cytokines released by these cells. This takes place in the context of a dysregulated dialogue between invading immune cells and target β cells, but the intracellular signals that decide β cell fate remain to be clarified. Alternative splicing (AS) is a complex post-transcriptional regulatory mechanism affecting gene expression. It regulates the inclusion/exclusion of exons into mature mRNAs, allowing individual genes to produce multiple protein isoforms that expand the proteome diversity. Functionally related transcript populations are co-ordinately spliced by master splicing factors, defining regulatory networks that allow cells to rapidly adapt their transcriptome in response to intra and extracellular cues. There is a growing interest in the role of AS in autoimmune diseases, but little is known regarding its role in T1D. In this review, we discuss recent findings suggesting that splicing events occurring in both immune and pancreatic β cells contribute to the pathogenesis of T1D. Splicing switches in Tcells and in lymph node stromal cells are involved in the modulation of the immune response against β cells, while β cells exposed to pro-inflammatory cytokines activate complex splicing networks that modulate β cell viability, expression of neoantigens and susceptibility to immune-induced stress. Unveiling the role of AS in β cell functional loss and death will increase our understanding of T1D pathogenesis and may open new avenues for disease prevention and therapy.

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Zinc‐induced modulation of SRSF6 activity alters Bim splicing to promote generation of the most potent apoptotic isoform BimS

Cited by 21 publications

References 46 publications

PGE2 Promotes Apoptosis Induced by Cytokine Deprivation through EP3 Receptor and Induces Bim in Mouse Mast Cells

PGE2 Promotes Apoptosis Induced by Cytokine Deprivation through EP3 Receptor and Induces Bim in Mouse Mast Cells

Intron Retention in the 5′UTR of the Novel ZIF2 Transporter Enhances Translation to Promote Zinc Tolerance in Arabidopsis

MECHANISMS IN ENDOCRINOLOGY: Alternative splicing: the new frontier in diabetes research

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