13033
2013
eng
e50695
2
8
article
1
2016-03-18
--
--
Accumulation of Splice Variants and Transcripts in Response to PI3K Inhibition in T Cells
Background
Measles virus (MV) causes T cell suppression by interference with phosphatidylinositol-3-kinase (PI3K) activation. We previously found that this interference affected the activity of splice regulatory proteins and a T cell inhibitory protein isoform was produced from an alternatively spliced pre-mRNA.
Hypothesis
Differentially regulated and alternatively splice variant transcripts accumulating in response to PI3K abrogation in T cells potentially encode proteins involved in T cell silencing.
Methods
To test this hypothesis at the cellular level, we performed a Human Exon 1.0 ST Array on RNAs isolated from T cells stimulated only or stimulated after PI3K inhibition. We developed a simple algorithm based on a splicing index to detect genes that undergo alternative splicing (AS) or are differentially regulated (RG) upon T cell suppression.
Results
Applying our algorithm to the data, 9% of the genes were assigned as AS, while only 3% were attributed to RG. Though there are overlaps, AS and RG genes differed with regard to functional regulation, and were found to be enriched in different functional groups. AS genes targeted extracellular matrix (ECM)-receptor interaction and focal adhesion pathways, while RG genes were mainly enriched in cytokine-receptor interaction and Jak-STAT. When combined, AS/RG dependent alterations targeted pathways essential for T cell receptor signaling, cytoskeletal dynamics and cell cycle entry.
Conclusions
PI3K abrogation interferes with key T cell activation processes through both differential expression and alternative splicing, which together actively contribute to T cell suppression.
PLoS ONE
10.1371/journal.pone.0050695
urn:nbn:de:bvb:20-opus-130335
PLoS ONE 8(2): e50695. doi:10.1371/journal.pone.0050695
Alice Riedel
Boitumelo Mofolo
Elita Avota
Sibylle Schneider-Schaulies
Ayton Meintjes
Nicola Mulder
Susanne Kneitz
eng
uncontrolled
T cells
eng
uncontrolled
gene regulation
eng
uncontrolled
alternative splicing
eng
uncontrolled
measles virus
eng
uncontrolled
T cell receptors
eng
uncontrolled
reverse transcriptase-polymerase chain reaction
eng
uncontrolled
cell cycle and cell division
eng
uncontrolled
TCR signaling cascade
Biowissenschaften; Biologie
open_access
Institut für Virologie und Immunbiologie
Theodor-Boveri-Institut für Biowissenschaften
Förderzeitraum 2012
Universität Würzburg
6615
2013
eng
article
1
2013-05-21
--
--
Accumulation of Splice Variants and Transcripts in Response to PI3K Inhibition in T Cells
Background: Measles virus (MV) causes T cell suppression by interference with phosphatidylinositol-3-kinase (PI3K) activation. We previously found that this interference affected the activity of splice regulatory proteins and a T cell inhibitory protein isoform was produced from an alternatively spliced pre-mRNA. Hypothesis: Differentially regulated and alternatively splice variant transcripts accumulating in response to PI3K abrogation in T cells potentially encode proteins involved in T cell silencing. Methods: To test this hypothesis at the cellular level, we performed a Human Exon 1.0 ST Array on RNAs isolated from T cells stimulated only or stimulated after PI3K inhibition. We developed a simple algorithm based on a splicing index to detect genes that undergo alternative splicing (AS) or are differentially regulated (RG) upon T cell suppression. Results: Applying our algorithm to the data, 9% of the genes were assigned as AS, while only 3% were attributed to RG. Though there are overlaps, AS and RG genes differed with regard to functional regulation, and were found to be enriched in different functional groups. AS genes targeted extracellular matrix (ECM)-receptor interaction and focal adhesion pathways, while RG genes were mainly enriched in cytokine-receptor interaction and Jak-STAT. When combined, AS/RG dependent alterations targeted pathways essential for T cell receptor signaling, cytoskeletal dynamics and cell cycle entry. Conclusions: PI3K abrogation interferes with key T cell activation processes through both differential expression and alternative splicing, which together actively contribute to T cell suppression.
urn:nbn:de:bvb:20-opus-77917
7791
In: PLoS ONE 8(2): e50695. doi:10.1371/journal.pone.0050695
Alice Riedel
Boitumelo Mofolo
Elita Avota
Sibylle Schneider-Schaulies
Ayton Meintjes
Nicola Mulder
Susanne Kneitz
deu
swd
Biologie
Medizin und Gesundheit
open_access
Theodor-Boveri-Institut für Biowissenschaften
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/6615/068_journal.pone.0050695.pdf