A step closer in defining glycosylphosphatidylinositol anchored proteins role in health and glycosylation disorders

Abstract

Glycosylphosphatidylinositol anchored proteins (GPI-APs) represent a class of soluble proteins attached to the external leaflet of the plasma membrane by a post-translation modification, the GPI anchor. The 28 genes currently involved in the synthesis and remodelling of the GPI anchor add to the ever-growing class of congenital glycosylation disorders. Recent advances in next generation sequencing technology have led to the discovery of Mabry disease and CHIME syndrome genetic aetiology. Moreover, with each described mutation known phenotypes expand and new ones emerge without clear genotype-phenotype correlation. A protein database search was made for human GPI-APs with defined pathology to help building-up a physio-pathological mechanism from a clinical perspective. GPI-APs function in vitamin-B6 and folate transport, nucleotide metabolism and lipid homeostasis. Defining GPI-APs role in disease bears significant clinical implications.

GPI-AP: Unraveling a New Class of Malignancy Mediators and Potential Immunotherapy Targets

“…One possible explanation is direct attachment of GPI-AP to signaling transmembrane proteins within lipid rafts. This was proved by replacing the GPI anchor motif of differentiation-promoting neural cell adhesion molecule (NCAM) with the signal sequence from carcinoembryonic antigen (CEA), producing a hybrid protein with NCAM ectodomain, but CEA-like antidifferentiation activity (10). Another explanation is that these antibody-induced signaling events depend on the induction and coalescence of lipid raft nanoclusters.…”

“…Briefly, GPI biochemical pathway consists of three phases: GPI anchor synthesis, joining protein moiety to GPI anchor, and final remodeling (9). Most of the literature emphasized on the role of GPI-APs in neurological and congenital disorders (10). However, only a few of the numerous examples of GPI-APs were studied for their role in cancer pathogenesis.…”

Glucose-dependent miR-125b is a negative regulator of β-cell function

“…Moreover, our RIP-RNA-seq experiments have identified additional miR-125b targets involved in these processes. For example, PGAP3 encodes a glycophosphatidylinositol (GPI)-specific phospholipase A2 expressed in the Golgi critical for the association of GPI-anchored proteins and lipid rafts 56 and thus the regulation of signalling pathways 57 . Also, VPS29, VPS4B and RAB17 are involved in endosomal function which plays a pivotal and often overlooked role in several aspects of β-cell function, including receptor trafficking, signalling and/or degradation (i.e.…”

Endoplasmic Reticulum Export of GPI-Anchored Proteins

“…In mammalian cells, the GPI-AP family is represented by more than 150 different proteins including enzymes, adhesion molecules, receptors, protease inhibitors, transcytotic transporters, and complement regulators. Because of this wide range of key biological activities performed by GPI-APs, they have been found to be essential in processes such as embryogenesis, development, neurogenesis, fertilization, and the immune system, being involved in the development of prominent human diseases, including neurodegeneration and cancer, underscoring their clinical relevance [15,16]. The yeast Saccharomyces cerevisiae has more than 60 GPI-APs, which are essential for growth.…”

“…These mutations have been found in PIG (phosphatidyl inositol glycan) genes encoding enzymes involved in the biosynthesis and attachment of the GPI anchor, and PGAP (post GPI attachment to proteins) genes encoding GPI-anchor remodeling enzymes [12], most of them required for the efficient ER export of GPI-APs. To date, it has been reported mutations in at least 13 PIG and PGAP genes that cause GPI-associated congenital disorders [16]. All these disorders are autosomal recessive, except the PIG-A-associated disease which is X-linked recessive.…”