The Asthma-associated PER1-like domain-containing protein 1 (PERLD1) Haplotype Influences Soluble Glycosylphosphatidylinositol Anchor Protein (sGPI-AP) Levels in Serum and Immune Cell Proliferation

Abstract

Post-glycosylphosphatidylinositol (GPI) attachment to proteins 3, also known as PGAP3 or PERLD1 (PER1-like domain-containing protein 1), participates in the lipid remodeling process of glycosylphosphatidylinositol (GPI) anchor proteins during post-translational modification. Functional defect in PERLD1 was previously hypothesized to influence this process in T-cells and their subsequent activation and proliferation. This current study aims to functionally characterize PERLD1 genetic variants and relate this with human immune cells proliferation rate upon stimulation. We first showed the association between a PERLD1 tag-single nucleotide polymorphism (tagSNP), rs2941504, and the development of asthma in our study population. This association remained significant after conditioning for the other asthma-associated SNP rs8076131 that is also located within the 17q12–21 region. Subsequent sequencing of 40 unrelated Singapore Chinese individuals identified 12 more common PERLD1 SNPs (minor allele frequency > 5%) that are in linkage disequilibrium (LD, r2 > 0.8) with rs2941504. Through in vitro studies, 7 of these SNPs were found to form a functional haplotype that influences alternative splicing of PERLD1 transcript. This result was validated in human peripheral blood mononuclear cell (PBMC), where the minor haplotype (Hap2) was shown to be associated with significantly increased PERLD1 truncated transcript. Additionally, Hap2 was found to be related to increased levels of several soluble GPI-anchored proteins (such as sCD55 and sCD59) in serum. Elevated sCD55 in the serum was demonstrated to reduce the proliferation rate of PBMCs upon phytohaemagglutinin (PHA) stimulation. Taken together, the current study has shown a functional PERLD1 haplotype, which modifies PBMC sensitivity upon stimulation and may contribute to the individual’s susceptibility to allergic asthma.

The ERBB2 Exonic Variant Pro1170Ala Modulates Mitogen-Activated Protein Kinase Signaling Cascades and Associates with Allergic Asthma

“…Studies have demonstrated multiple polymorphisms in ORMDL3 are associated with childhood asthma, regulate ORMDL3 transcript expression, and correlate with changes in T helper 2 cytokines levels [49, 50]. Our group has also identified significant asthma-associated eQTLs in ORMDL3, PPP1R1B, ZPBP2, and GSDMB [21], as well as characterized the functional roles of PNMT and PERLD1 genes in asthma [18, 19]. As it remains uncertain which gene or combination of genes is important in chr17q12-21, future studies in mice deficient in these candidate genes might provide further understanding on this question.…”

“…Our group has previously identified 7 asthma-associated tag-single nucleotide polymorphisms (tag-SNPs) in the 17q12 locus that includes the PPP1R1B , STARD3 , PNMT , PERLD1 , and ERBB2 genes [17]. Of these genes, the functional roles of PNMT and PERLD1 genes in asthma have been previously characterized [18, 19]. However, the functional implications of ERBB2 SNPs in the pathogenesis process of asthma remain uncertain.…”

PGAP3 regulates human bronchial epithelial cell mRNAs present in asthma and respiratory virus reference data sets

“…PGAP3 (Post-GPI Attachment to Proteins 3) (also known as PERLD1 9 and PER1 12 ) is a chr:17q12-21 localized gene that encodes a glycosylphosphatidylinositol (GPI)-specific phospholipase that primarily localizes to the Golgi apparatus 12 , but can also be detected in the plasma membrane and cytosol (data from Human Protein Atlas v23.proteinatlas.org: https://www.proteinatlas.org/ENSG00000161395-PGAP3 ) 13 . PGAP3 encodes a seven-transmembrane protein in the Golgi that removes unsaturated fatty acids from the sn-2 position of GlycosylPhosphatidyliInositol (GPI) 12 .…”

“…The GPI anchor is formed in the ER, transported to the Golgi for fatty acid remodeling and cellular export to lipid rafts in the cell membrane 12,13 . The PGAP3 SNP 504 linked to asthma 9 has also been associated with peripheral blood mononuclear cell surface and secreted GPI-AP levels 9 , underscoring a potential mechanistic link between PGAP3, GPI-AP, and lipid rafts. Although there are no studies of the function of PGAP3 related to asthma, PGAP3 is known to regulate lipid rafts 14 that contain GPI-AP, receptors, adhesion molecules, signaling molecules, and enzymes of potential importance to asthma.…”

Interaction of Full-Length Glycosylphosphatidylinositol-Anchored Proteins with Serum Proteins and Their Translocation to Cells In Vitro Depend on the (Pre-)Diabetic State in Rats and Humans

“…Since the first identification of GPI-anchored proteins (GPI-APs) [ 7 , 8 ], it has been speculated that this type of membrane anchorage could favor their spontaneous nonenzymic release from plasma membranes (see [ 9 , 10 ] for reviews). This has to be discriminated from the enzymic release, which has been amply documented in the past [ 11 , 12 ]. The possibility of spontaneous release was supported by the considerably lower forces of binding to and extraction from supported phospholipid/cholesterol mono- and bilayers for GPI-APs compared to transmembrane proteins as measured in various biophysical studies [ 13 , 14 , 15 , 16 , 17 ].…”