Unremodeled GPI-anchored proteins at the plasma membrane trigger aberrant endocytosis.

The plasma membrane has a complex organization that includes the polarized distribution of membrane proteins and lipids. Glycosylphosphatidylinositol-anchored proteins (GPI-APs) are ubiquitously expressed in eukaryotes and represent a functionally diverse, extensively remodeled, ER-derived group of proteins critical for the organization and function of the plasma membrane. Little is known about how the transport of incompletely remodeled GPI-APs to the plasma membrane affects cell function. Here, we investigated how failure to remodel mannose 2 (Man2) of the GPI moiety impacted endocytic activity on the plasma membrane. We find that Man2 unremodeled GPI-APs increased membrane disorder and generated a stress response that triggered abnormal ubiquitin- and clathrin-dependent endocytosis. The resulting stress-induced endocytosis disrupted the trafficking repertoire of a subset of plasma membrane proteins, which were redirected, via the multivesicular body, to numerous small vacuoles for degradation. Our findings highlight the critical importance of GPI-AP Man2 remodeling for maintaining the integrity and homeostasis of the plasma membrane.