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Proprotein Convertase Subtilisin/Kexin Type 7 (PCSK7) Is Essential for the Zebrafish Development and Bioavailability of Transforming Growth Factor β1a (TGFβ1a)

ABSTRACT: Proprotein convertase subtilisin/kexin (PCSK) enzymes convert proproteins into bioactive end products. Although other PCSK enzymes are known to be essential for biological processes ranging from cholesterol metabolism to host defense, the in vivo importance of the evolutionarily ancient PCSK7 has remained enigmatic. Here, we quantified the expressions of all pcsk genes during the 1st week of fish development and in several tissues. pcsk7 expression was ubiquitous and evident already during the early development. To compare mammalian and zebrafish PCSK7, we prepared homology models, which demonstrated remarkable structural conservation. When the PCSK7 function in developing larvae was inhibited, we found that PCSK7-deficient fish have defects in various organs, including the brain, eye, and otic vesicle, and these result in mortality within 7 days postfertilization. A genome-wide analysis of PCSK7-dependent gene expression showed that, in addition to developmental processes, several immune system-related pathways are also regulated by PCSK7. Specifically, the PCSK7 contributed to the mRNA expression and proteolytic cleavage of the cytokine TGFβ1a. Consequently, tgfβ1a morphant fish displayed phenotypical similarities with pcsk7 morphants, underscoring the importance of this cytokine in the zebrafish development. Targeting PCSK activity has emerged as a strategy for treating human diseases. Our results suggest that inhibiting PCSK7 might interfere with normal vertebrate development.

ORGANISM(S): Danio rerio

PROVIDER: GSE42070 | GEO | 2014/01/02

SECONDARY ACCESSION(S): PRJNA179078

REPOSITORIES: GEO

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Project description:Purpose: FURIN is a member of the proprotein convertase subtilisin/kexin (PCSK) family of serine endoproteases important in converting immature proproteins into their functional form. While FURIN is important in various aspects of the immune response such as in CD4+ T cells, FURIN´s role in CD8+ T cells is unclear. Here, we isolated naive CD8+ T cells from conditional T cell specific Furin KO (Cd4-Cre-Furinflox/flox) and WT (Furinflox/flox) mice and studied the genome-wide gene expression pattern upon in vitro anti-CD3/anti-CD28 activation (plate-bound, 5µg/ml each) using RNA sequencing. We also used recombinant TGFB1 (0.5ng/ml) or IL12 (10ng/ml) in the same experimental setting to study their impact on the CD8+ T cell transcriptome. Methods: Total RNA was isolated from the stimulated CD8+ T cells and the RNA-sequencing data was produced by the Functional Genomics Unit of the HiLIFE Genome Analysis Infrastructure (University of Helsinki, Helsinki, Finland) using Illumina NextSeq High Output 1x75 bp. Data processing pipeline was built on Snakemake wrappers, and used STAR to quantify features from quality and adapter trimmed reads in gene level. Prior the normalisation and differential gene expression analysis with DESeq2, the matrix of raw gene counts was prefiltered to keep only rows that have at least 10 reads in total. Result tables were annotated with biomaRt. Results: Snakemake preprocessing pipeline measured 55573 genes against GRCm38, ENSEMBL release 97. 17714 of them was used for statistical testing. Full result tables for each treatment were ranked by p-value and the normalized DESeq2 abundances in samples were included. The genes with BH-adjusted p-value <0.05 was considered differentially expressed. Conclusions: Our study revealed that the abscence of FURIN influences the expression of several genes in activated CD8+ T cells. Additionally, although FURIN-deficient CD8+ T cells can respond to exogenous TGFB1 and IL12, administrating these cytokines further increases the number of differentially expressed genes between Furin KO and WT CD8+ T cells.

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Proprotein Convertase Subtilisin/Kexin Type 7 (PCSK7) Is Essential for the Zebrafish Development and Bioavailability of Transforming Growth Factor β1a (TGFβ1a)

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