Splicing factors differentially expressed in psoriasis alter mRNA maturation of disease-associated EDA+ fibronectin

Abstract

The EDA+ fibronectin splicing variant is overexpressed in psoriatic non-lesional epidermis and sensitizes keratinocytes to mitogenic signals. However, regulation of its abundance is only partially understood. In our recent cDNA microarray experiment, we identified three SR-rich splicing factors-splicing factor, arginine/serine-rich 18 (SFRS18), peptidyl-prolyl cis-trans isomerase G (PPIG), and luc-7 like protein 3 (LUC7L3)-which might be implicated in the preactivated states of keratinocytes in psoriatic non-involved skin and could also contribute to the regulation of fibronectin mRNA maturation. In this study, we investigated the role of LUC7L3, PPIG, and SFRS18 in psoriasis and in the mRNA maturation process of fibronectin. Regarding tissue staining experiments, we were able to demonstrate a characteristic distribution of the splicing factors in healthy, psoriatic non-involved and involved epidermis. Moreover, the expression profiles of these SR-rich proteins were found to be very similar in synchronized keratinocytes. Contribution of splicing facwwtors to the EDA+ fibronectin formation was also confirmed: their siRNA silencing leads to altered fibronectin mRNA and protein expression patterns, suggesting the participation in the EDA domain inclusion. Our results indicate that LUC7L3, PPIG, and SFRS18 are not only implicated in EDA+ fibronectin formation, but also that they could possess multiple roles in psoriasis-associated molecular abnormalities.

Analysis of psoriasis‐relevant gene expression and exon usage alterations after silencing of SR‐rich splicing regulators

“…In our previous work, we verified that, similarly to other SR‐rich proteins (such as SF2/ASF), LUC7L3, PPIG and SFRS18 also facilitate inclusion of the EDA domain . We were able to validate the significant changes of EDA+/EDA– fibronectin abundances in our present large‐scale experiment as well . In addition to differential splicing of fibronectin, we also demonstrated the significant upregulation of ITGA5, a fibronectin receptor.…”

“…In subsequent experiments, we successfully verified that the aforementioned splicing regulators are able to facilitate EDA domain inclusion. Data mining using publicly available interaction databases also supported the credibility of the interaction of LUC7L3 and SFRS18 splicing regulators . These data suggest that these splicing factors indeed contribute to disease pathogenesis and their effect is—at least partially—mediated by the regulation of psoriasis‐associated EDA+ fibronectin.…”

“…LUC7L3 and SFRS18 splicing factors have been selected based on the results of the aforementioned cDNA microarray experiment, where we identified genes showing T‐lymphokine‐induced differential expression among control and psoriatic non‐involved epidermis . Products encoded by LUC7L3 and SFRS18 genes are both SR‐rich splicing regulators.…”

“…In this study, we aim to determine additional molecular pathways influenced by the SR‐rich splicing regulators, LUC7L3 and SFRS18, as the combined effects of these two genes proved to be the most potent in prior experiments . Global transcriptome analysis was performed using pair‐end RNA‐Sequencing (RNA‐Seq) to define gene expression changes and differential exon usage in human papillomavirus (HPV)‐immortalised keratinocytes.…”

The abnormal regulation of spliceosome may be a key factor for coronary heart disease: a simple bioinformatics analysis

“…PNISR, also known as SFRS18. Data mining using publicly available interaction databases also supported the credibility of the interaction of LUC7L3 and SFRS18 splicing regulators [42] . Previous paper has reported that these splicing factors indeed contribute to disease pathogenesis and their effect is-at least partially-mediated by the regulation of psoriasis-associated EDA+ bronectin [43] .…”