GPLD1 functions as a scavenger chaperone mediating lysosomal degradation of extracellular aberrant proteins

Abstract

Loss of proteostasis leads to the accumulation of aberrant proteins, including aggregated proteins and amyloid fibrils, contributing to various diseases. Protein quality control systems are essential for maintaining proteostasis. Although intracellular mechanisms are well characterized, pathways responsible for degradation of aberrant proteins outside the cell remain poorly understood. We previously identified the chaperone/carrier- and receptor-mediated extracellular protein degradation (CRED) pathway, in which the extracellular chaperone clusterin binds misfolded proteins and the resulting complex is delivered to lysosomes via endocytosis. However, it remains unclear whether other factors are involved in this pathway. To identify novel regulators, plasma factors binding serum amyloid A1 (SAA1) were investigated. Glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1) was found to directly bind SAA1 and promote its lysosomal degradation. This activity was independent of GPLD1s cleavage activity for GPI-anchored proteins. Furthermore, GPLD1 mediates lysosomal degradation of misfolded proteins, with cell surface heparan sulfate acting as its receptor. Our data demonstrate that GPLD1 is a novel scavenger carrier with substrate specificity distinct from clusterin, responsible for degrading extracellular aberrant proteins.