Alpha 2-macroglobulin acts as a clearance factor in the lysosomal degradation of extracellular misfolded proteins

Proteostasis regulates protein folding and degradation; its maintenance is essential for resistance to stress and aging. The loss of proteostasis is associated with many age-related diseases. Within the cell, molecular chaperones facilitate the refolding of misfolded proteins into their bioactive forms, thus preventing undesirable interactions and aggregation. Although the mechanisms of intracellular protein degradation pathways for intracellular misfolded proteins have been extensively studied, the protein degradation pathway for extracellular proteins remain poorly understood. In this study, we identified several misfolded proteins that are substrates for alpha 2-macroglobulin (α₂M), an extracellular chaperone. We also established a lysosomal internalization assay for α₂M, which revealed that α₂M mediates the lysosomal degradation of extracellular misfolded proteins. Comparative analyses of α₂M and clusterin, another extracellular chaperone, indicated that α₂M preferentially targets aggregation-prone proteins. Thus, we present the degradation pathway of α2M, which interacts with aggregation-prone proteins for lysosomal degradation via selective internalization.