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Tutanov et al. Extracell Vesicles Circ Nucleic Acids 2023;4:195-217 https://dx.doi.org/10.20517/evcna.2023.17 Page 203

Figure 3. GPI anchor biosynthesis in the Golgi and trafficking to the plasma membrane. Steps for GPI anchor modification and trafficking
from the ER to the plasma membrane are shown [44] . The yellow box denotes an N-acetylgalactosamine, whereas the yellow circle
denotes a galactose. GPI-APs preferentially reside in lipid raft-rich areas, as is depicted both in the Golgi and at the plasma membrane.

Figure 4. GPI-APs can be sorted to apical cell surface through two distinct mechanisms. The left side depicts the lipid-based sorting
mechanism in the Golgi, where remodeling of GPI-APs allows for clustering into lipid-ordered domains that leads to apical sorting. The
right side depicts the oligomerization-based sorting mechanism in the Golgi, where oligomerization of GPI-APs through ectodomain
interactions allows for clustering and sorting to the apical cell surface.

two saturated fatty acids by the GPI anchor through GPI-lipid remodeling in the Golgi, which leads to the
recovery of GPI-APs with DRMs [52,53] and the fact that the apical membrane is enriched in saturated lipids
such as sphingolipids, which are made in the Golgi, and cholesterol [37,60] . Supporting this lipid-based sorting
mechanism, inhibitors of sphingolipid biosynthesis and/or removal of cholesterol have been shown to
impair the apical sorting of GPI-Aps [61,62] . In contrast, another report has shown that the lipids of GPI-APs
that have not been remodeled in the Golgi can still be transported to the plasma membrane with the same
efficiency as remodeled GPI-APs with saturated fatty acids .
[63]

These reports spurred the search for alternative pathways that may also regulate apical targeting such as
oligomerization of GPI-APs, which has also been suggested as a key factor in the apical sorting of GPI-APs.
GPI-APs are known to form high molecular weight complexes during their transport to the apical
membrane, and this process of oligomerization is crucial for proper sorting to the apical domain.
Impairment of this oligomerization leads to the missorting of GPI-APs to the basolateral domain [62,64] .