Ethanolamine-phosphate on the second mannose is the preferential bridge for some of the brain GPI-anchored proteins

Abstract

Glycosylphosphatidylinositols (GPIs) are glycolipids that anchor many proteins (GPI-APs) on the cell surface. GPI precursor has three mannoses, which in mammalian cells, are all modified by the addition of ethanolamine-phosphate (EthN-P). It is postulated that EthN-P on the third mannose (EthN-P-Man3) is the bridge between GPI to the protein and the second (EthN-P-Man2) is removed after GPI-protein attachment. However, EthN-P-Man2 may not be always transient as postulated, as mutations of PIGG, the enzyme that transfers EthN-P to Man2, result in inherited GPI deficiencies (IGDs), characterized by neuronal dysfunctions. We hypothesized that EthN-P-Man2 plays a role beyond what is now postulated. Indeed, EthN-P on Man2 is not only the alternate bridge in some GPI-APs but the actual bridge in others, among them, the ect-5’-nucleotidase and netrin G2. We found that CD59, a GPI-AP, is attached via EthN-P-Man2 in both PIGB-knockout cells, in which GPI lacks Man3 and with a small fraction, in wild type cells. Our findings modify the current view of GPI anchoring and provide mechanistic bases of IGDs caused by PIGG mutations.

Requirement of sequential hydrolysis by CD73 and ALP for uptake of vitamin B2 into cells

“…This is consistent with reports that some severe IGD cases show mitochondrial dysfunction (Tarailo-Graovac et al, 2015). CD73 expression is decreased in phosphatidylinositol glycan anchor biosynthesis class G (PIGG) knockout cells (Ishida et al, 2022) and some cases with null mutation of PIGG also showed decreased expression of CD73 and mitochondrial dysfunction (Tremblay- Laganière et al, 2021), suggesting that CD73 expression is important for uptake of vitamin B 2 in PIGG deficiency. Similar to HPP, some patients with IGD show decreased vitamin B 6 uptake and suffer from pyridoxine-dependent seizures (Kuki et al, 2013).…”