The three as: Alternative splicing, alternative polyadenylation and their impact on apoptosis in immune function

Blake, Davia; Lynch, Kristen W.

doi:10.1111/imr.13018

Cited by 25 publications

(17 citation statements)

References 229 publications

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“…Any error in this process may lead to the destruction of normal cell functions and the occurrence of diseases. In particular, immune-related genes are also regulated by SFs, which can cause changes in immune response or immune cell composition ( Blake and Lynch, 2021 ). SFs may be the basis for identifying new diagnostic and prognostic biomarkers and new treatment strategies.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Identification of Immune-Related Alternative Splicing and Splicing Regulators Involved in Abdominal Aortic Aneurysm

Liu

Chen

et al. 2022

Front. Genet.

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The molecular mechanism of AAA formation is still poorly understood and has not been fully elucidated. The study was designed to identify the immune-related genes, immune-RAS in AAA using bioinformatics methods. The GSE175683 datasets were downloaded from the GEO database. The DEseq2 software was used to identify differentially expressed genes (DEGs). SUVA pipeline was used to quantify AS events and RAS events. KOBAS 2.0 server was used to identify GO terms and KEGG pathways to sort out functional categories of DEGs. The CIBERSORT algorithm was used with the default parameter for estimating immune cell fractions. Nine samples from GSE175683 were used to construct the co-disturbed network between expression of SFs and splicing ratio of RAS events. PCA analysis was performed by R package factoextra to show the clustering of samples, and the pheatmap package in R was used to perform the clustering based on Euclidean distance. The results showed that there were 3,541 genes significantly differentially expressed, of which 177 immune-related genes were upregulated and 48 immune-related genes were downregulated between the WT and WTA group. Immune-RAS events were mainly alt5P and IR events, and about 60% of it was complex splicing events in AAA. The WT group and the WTA group can be clearly distinguished in the first principal component by using the splicing ratio of immune-RAS events. Two downregulated genes, Nr4a1 and Nr4a2, and eight upregulated genes, Adipor2, Akt2, Bcl3, Dhx58, Pparg, Ptgds, Sytl1, and Vegfa were identified among the immune-related genes with RAS and DEGs. Eighteen differentially expressed SFs were identified and displayed by heatmap. The proportion of different types of cells and ratio of the average ratio of different cells were quite different. Both M1 and M2 types of macrophages and plasma cells were upregulated, while M0 type was downregulated in AAA. The proportion of plasma cells in the WTA group had sharply increased. There is a correlation between SF expression and immune cells/immune-RAS. Sf3b1, a splicing factor with significantly different expression, was selected to bind on a mass of immune-related genes. In conclusion, our results showed that immune-related genes, immune-RAS, and SFs by genome-wide identification were involved in AAA.

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Section: Discussionmentioning

confidence: 99%

Genome-Wide Identification of Immune-Related Alternative Splicing and Splicing Regulators Involved in Abdominal Aortic Aneurysm

Liu

Chen

et al. 2022

Front. Genet.

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“…Thus, there is a possibility that CAR-T cell activation (via the CAR CD28-costimulatory domain) may be altered following binding/sequestration of nuclear PFS by VL30 mRNA. [87-89]…”

Section: Discussionmentioning

confidence: 99%

“…Thus, there is a possibility that CAR-T cell activation (via the CAR CD28-costimulatory domain) may be altered following binding/sequestration of nuclear PFS by VL30 mRNA. [87][88][89] Notwithstanding these biosafety concerns, more than a thousand patients with incurable oncologic diseases have been successfully treated with CAR-T cells. [90,91] To date, not a single clinical report has described proliferative abnormalities that could be attributed to the inadvertent contamination of therapeutic T-cells with VL30 genomes.…”

Section: Discussionmentioning

confidence: 99%

Inadvertent Transfer of Murine VL30 Retrotransposons to CAR-T Cells

Lee

Gui

Dotti

et al. 2022

Preprint

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For more than a decade genetically engineered autologous T-cells have been successfully employed as immunotherapy drugs for patients with incurable blood cancers. The active component in some of these game-changing medicines are autologous T-cells that express viral vector- delivered chimeric antigen receptors (CARs), which specifically target proteins that are preferentially expressed on cancer cells. Some of these therapeutic CAR expressing T-cells (CAR-Ts) are engineered via transduction with γ-retroviral vectors (γ-RVVs) produced in a stable producer cell line that was derived from murine PG13 packaging cells (ATCC CRL-10686). Earlier studies reported on the co-packaging of murine virus-like 30S RNA (VL30) genomes with γ- retroviral vectors generated in murine stable packaging cells. In an earlier study VL30 mRNA was found to enhance the metastatic potential of human melanoma cells. These findings raise biosafety concerns regarding the possibility that therapeutic CAR-Ts have been inadvertently contaminated with potentially oncogenic VL30 retrotransposons. In this study, we demonstrated the presence of infectious VL30 particles in PG13 cells conditioned media and observed the ability of these particles to deliver transcriptionally active VL30 genomes to human cells. Notably, VL30 genomes packaged by HIV-1-based vector particles transduced naïve human cells in culture. Furthermore, we detected transfer and expression of VL30 genomes in clinical-grade CAR-Ts generated by transduction with PG13 cells-derived γ-retroviral vectors. Our findings raise biosafety concerns regarding the use of murine packaging cell lines in ongoing clinical applications.

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“…Like FAS, the gene encoding Bcl-x is alternatively spliced to produce two isoforms: Bcl-xS, which promotes the activity of Bax and apoptosis, and a longer isoform, Bcl-xL that inhibits Bax activity and thus is anti-apoptotic (Billen et al, 2008; Stevens and Oltean, 2019). Bax and Bim also have reported alternatively spliced isoforms; however, the functional relevance of these is less well characterized (Blake and Lynch, 2021). Finally, once released from the mitochondria, cytosolic cytochrome c activates the enzymatic activity of the initiator caspase-9, through formation of the apoptosome, which then also cleaves the afore-mentioned effector caspases to promote apoptosis (McIlwain et al, 2013; Singh et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…Consequently, differences in the ratio of isoforms generated by alternative splicing can impact overall cellular activity (Baralle and Giudice, 2017;Ule and Blencowe, 2019). Some of the best characterized examples of how alternative splicing can switch protein activity and cellular function come from the apoptosis signaling pathway (Blake and Lynch, 2021).…”

Section: Introductionmentioning

confidence: 99%

Alternative Splicing of Apoptosis Genes Promotes Human T Cell Survival

Blake

Radens

Ferretti

et al. 2022

Preprint

Self Cite

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Alternative splicing occurs in the vast majority of human genes, giving rise to distinct mRNA and protein isoforms. We, and others, have previously identified hundreds of genes that change their isoform expression upon T cell activation via alternative splicing; however, how these changes link activation input with functional output remains largely unknown. Here we investigate how costimulation of T cells through the CD28 receptor impacts alternative splicing in T cells activated through the T cell receptor (CD3) and find that while CD28 signaling alone has minimal impact on splicing, it enhances the extent of change for up to 20% of TCR-induced alternative splicing events. Interestingly, a set of CD28-enhanced splicing events occur within genes encoding key components of the apoptotic signaling pathway; namely caspase-9, Bax and Bim. Using both CRISPR-edited cells and antisense oligos to force expression of specific isoforms, we show for all three of these genes that the isoform induced by CD3/CD28 costimulation promotes resistance to apoptosis, and that changes in all three genes together function combinatorially to further promote cell viability. Finally, we show that the JNK signaling pathway, induced downstream of CD3/CD28 costimulation, is required for each of these splicing events, further highlighting their co-regulation. Together these findings demonstrate that alternative splicing is a key mechanism by which costimulation of CD28 promotes viability of activated T cells.

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The three as: Alternative splicing, alternative polyadenylation and their impact on apoptosis in immune function

Abstract: This article is part of a series of reviews covering RNA Regulation in Immunity appearing in Volume 304 of Immunological Reviews.

Cited by 25 publications

References 229 publications

Genome-Wide Identification of Immune-Related Alternative Splicing and Splicing Regulators Involved in Abdominal Aortic Aneurysm

Genome-Wide Identification of Immune-Related Alternative Splicing and Splicing Regulators Involved in Abdominal Aortic Aneurysm

Inadvertent Transfer of Murine VL30 Retrotransposons to CAR-T Cells

Alternative Splicing of Apoptosis Genes Promotes Human T Cell Survival

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