(Patho)Physiology of Glycosylphosphatidylinositol-Anchored Proteins I: Localization at Plasma Membranes and Extracellular Compartments

Abstract

Glycosylphosphatidylinositol (GPI)-anchored proteins (APs) are anchored at the outer leaflet of plasma membranes (PMs) of all eukaryotic organisms studied so far by covalent linkage to a highly conserved glycolipid rather than a transmembrane domain. Since their first description, experimental data have been accumulating for the capability of GPI-APs to be released from PMs into the surrounding milieu. It became evident that this release results in distinct arrangements of GPI-APs which are compatible with the aqueous milieu upon loss of their GPI anchor by (proteolytic or lipolytic) cleavage or in the course of shielding of the full-length GPI anchor by incorporation into extracellular vesicles, lipoprotein-like particles and (lyso)phospholipid- and cholesterol-harboring micelle-like complexes or by association with GPI-binding proteins or/and other full-length GPI-APs. In mammalian organisms, the (patho)physiological roles of the released GPI-APs in the extracellular environment, such as blood and tissue cells, depend on the molecular mechanisms of their release as well as the cell types and tissues involved, and are controlled by their removal from circulation. This is accomplished by endocytic uptake by liver cells and/or degradation by GPI-specific phospholipase D in order to bypass potential unwanted effects of the released GPI-APs or their transfer from the releasing donor to acceptor cells (which will be reviewed in a forthcoming manuscript).

Bone marrow stromal cell antigen 2: Tumor biology, signaling pathway and therapeutic targeting (Review)

“…BST2 contains a lipid raft in the GPI anchor motif and the TM domain ( 32 , 36 ). The GPI site can affect the transduction of cellular activation or inhibition signals, resulting in Ca 2+ fluxes, protein tyrosine phosphorylation or cytokine secretion ( 37 , 38 ). The highly conserved YxY motif in the cytoplasmic region is important in nuclear factor (NF)-κB activation and for association with the actin cytoskeleton ( 34 , 39 ).…”

(Patho)Physiology of Glycosylphosphatidylinositol-Anchored Proteins II: Intercellular Transfer of Matter (Inheritance?) That Matters

“…Thus, LDs represent a perfect environment for displaying full-length GPI-APs at their surface through insertion of their anchor into the phospholipid monolayer. The apparent translocation of GPI-APs from PMs to cytoplasmic LDs in adipocytes may represent a mechanism leading to the incorporation of GPI-APs onto the surface of other lipophilic particles such as surfactant-like particles (SLPs), milk fat globules (MFGs), and nodal vesicular particles (NVPs) (for a review, see [ 6 , 27 ]). It remains to be clarified whether the localization GPI-APs at SLPs and MFGs is restricted to their surface, i.e., the outer leaflet of the phospholipid bilayer, or also holds true for the phospholipid monolayer of their lipophilic core, in addition.…”

“…In eukaryotic cells, a specific class of surface proteins is anchored at the outer leaflet of the phospholipid bilayer of plasma membranes (PMs) via a glycosylphosphatidylinositol (GPI) glycolipid moiety which encompasses about 150, i.e., 0.5–0.8%, of the translated proteins in mammals [ 1 , 2 ] (for a review dealing with the structure and biogenesis of GPI-APs, see [ 3 , 4 ]). One of the major characteristics of GPI-anchored proteins (GPI-APs) is their release from the PMs through a small set of phospholipases of unique substrate but different cleavage specificity (for a review, see [ 5 , 6 ]) rather than a large panel of proteases, each with a different substrate and unique cleavage specificity, as is required for transmembrane proteins (for a review, see [ 7 , 8 , 9 , 10 ]). An additional feature is their intercellular transfer, which relies on the complete GPI anchor remaining attached and special carrier mechanisms and structures, among them extracellular vesicles (EVs) and micelle-like complexes.…”

Actin cytoskeleton differently regulates cell surface organization of GPI-anchored proteins in polarized epithelial cells and fibroblasts

“…Glycosylphosphatidylinositol (GPI)-anchored proteins, attached to the external leaflet of the plasma membrane via their glycolipid anchor, represent 0.5% of total proteins in eukaryotes. In mammals, more than 150 GPI-APs have been identified, and they play diverse functions, ranging from enzymatic activity, cell adhesion, signaling, neuritogenesis, and immune response ( Lebreton et al, 2018 ; Müller and Müller, 2023 ).…”