Mechanisms of Quality Control in GPI-Anchored Proteins: The Central Role of the Lipid Anchor

Glycosylphosphatidylinositol-anchored proteins (GPI-APs) are a distinct class of eukaryotic cell-surface proteins characterized by a glycolipid anchor at their C-terminus. They display unique biophysical properties and play important roles in human diseases, including transmissible spongiform encephalopathies (TSEs), malaria, sleeping sickness, and rare disorders collectively termed inherited GPI deficiency (IGD). Because of their broad clinical relevance, GPI-APs have become a major focus of research, including their intracellular quality control (QC). Studies in diverse model organisms have revealed striking interspecies differences in GPI-AP QC pathways and notable distinctions from QC mechanisms and the degradation of misfolded species governing other secretory proteins. In this review, we summarize recent advances in the understanding of these cellular processes and propose that the observed variations in QC reflect distinct cellular strategies that balance protein QC with membrane homeostasis across evolutionary contexts.