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9.A.71 The Glycosylphosphatidylinositol-anchored Protein (GPI-AP) Family 

The exposure of phosphatidylserine (PS) on the cell surface is a general marker of apoptotic cells. Non-apoptotic PS externalization is induced by several activation stimuli, including engagement of immunoreceptors. Immune cells can also be activated by aggregation of glycosylphosphatidylinositol-anchored proteins (GPI-APs). These proteins lack transmembrane and cytoplasmic domains, but mediate PS externalization. Smrz et al. 2007 showed that GPI-APs in rodent mast cells induce a rapid and reversible externalization of PS by a non-apoptotic mechanism. PS externalization triggered by GPI-AP-specific monoclonal antibodies was dependent on the activity of H+-ATP synthase and several other enzymes involved in mast cell signaling. Disruption of actin cytoskeleton by latrunculin B or of plasma membrane integrity by methyl-beta-cyclodextrin had opposite effects on PS externalization triggered through GPI-AP or the high affinity IgE receptor. PS externalization mediated by GPI-APs was also observed in some other cells, and its extent varied with antibodies used. Effects of different antibodies on PS externalization were additive, indicating that independent stimuli converge onto a signaling pathways leading to PS externalization. This mechanism could contribute to 'inside-out' signaling in response to pathogens and other external activators and/or to initiation of other functions associated with PS externalization. These proteins may be distantly related to those in TC family 8.A.31.

Newly synthesized glycosylphosphatidylinositol-anchored proteins having a very long chain ceramide lipid moiety are clustered and sorted into specialized endoplasmic reticulum exit sites that are distinct from those used by transmembrane proteins. Furthermore, the chain length of ceramide in the endoplasmic reticulum membrane is critical for this sorting selectivity (Rodriguez-Gallardo et al. 2020).

The reaction catalyzed by GPI-AP is:

PS (in) ⇌ PS (out)

References associated with 9.A.71 family:

Rodriguez-Gallardo, S., K. Kurokawa, S. Sabido-Bozo, A. Cortes-Gomez, A. Ikeda, V. Zoni, A. Aguilera-Romero, A.M. Perez-Linero, S. Lopez, M. Waga, M. Araki, M. Nakano, H. Riezman, K. Funato, S. Vanni, A. Nakano, and M. Muñiz. (2020). Ceramide chain length-dependent protein sorting into selective endoplasmic reticulum exit sites. Sci Adv 6:. 33310842
Smrz, D., L. Dráberová, and P. Dráber. (2007). Non-apoptotic phosphatidylserine externalization induced by engagement of glycosylphosphatidylinositol-anchored proteins. J. Biol. Chem. 282: 10487-10497. 17284440