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Page 202 Tutanov et al. Extracell Vesicles Circ Nucleic Acids 2023;4:195-217 https://dx.doi.org/10.20517/evcna.2023.17

Figure 1. GPI-anchorage for DPEP1. DPEP1, a GPI-linked dipeptidase overexpressed in CRC, is used as an example of GPI anchorage. The
exact form of phosphatidylinositol is unknown [24] . Glycan core additions, apart from the mannose and glucosamine backbone alone that
makes up a fourth of the DPEP1 GPI anchor, are variable, with 9% of GPI anchors also having a sialic acid (not shown) [24] . Cleavage sites
on the GPI anchor for PI-PLC and PI-PLD are shown [40] .

Figure 2. GPI anchor biosynthesis in the ER. Steps for GPI anchor biosynthesis and protein anchoring are shown [44] . UDP denotes uracil
diphosphate, PE denotes phosphatidylethanolamine, signal peptide denotes an N-terminal signal peptide that is not required for GPI
anchorage, and GPI-SS denotes the GPI signal sequence that may be associated with the membrane before cleavage [45,46] . Step 3
involves an unknown mechanism that allows for the movement of the phosphatidylinositol to the luminal side of the ER. Step 4 involves
the addition of a fatty acid chain, while Step 5 involves lipid remodeling. Step 13 involves the cleavage of the GPI-SS and the addition of
the protein onto the preassembled GPI anchor. The anchor is further modified and is released from a COPII-coated vesicle for trafficking
to the Golgi.

to the apical domain, respectively [54-57] . In most polarized epithelial cells, the GPI anchor appears to act as an
apical sorting signal, as most GPI-APs are delivered in specific secretory vesicles from the TGN to the apical
[58]
but not to the basolateral cell surface . Several mechanisms facilitating apical sorting have been described
in the literature, with the main ones being lipid-based sorting and oligomerization-based sorting [Figure 4].
The lipid-based sorting mechanism suggests that remodeling of the GPI-lipid in the Golgi causes GPI-APs
to cluster and associate with sphingolipids and cholesterol, facilitated by the two saturated fatty acids .
[59]
These specialized lipid-ordered domains then serve as selective platforms for vesicle budding at the
TGN [35,51] . Lipid-based sorting is based on the observation that the sorting correlates with the acquisition of