BAG2 Condensates Couple Proteostasis to CD8 + T Cell Surveillance

SUMMARY Protein aggregation, impaired degradation, and immune activation are central hallmarks of neurodegenerative diseases, yet how these processes are coordinated remains unclear. Here, we identify Immune-Protein Degradation Bodies (I-PDBs), a previously unrecognized class of BAG2-driven, phase-separated organelles that integrate protein quality control with adaptive immunity. IFNγ induce I-PDB formation at the endoplasmic reticulum (ER), where they concentrate immunoproteasome components, MHC-I peptide-loading machinery, and ER-associated chaperones. I-PDBs redirect proteostatic cargo from centrosomal aggregation pathways to spatially restricted degradation sites optimized for antigenic peptide generation, coupling selective substrate clearance to CD8⁺ T cell engagement. Using a cellular model of aggregation-prone tau, we show that I-PDBs capture pathological tau fibrils at ER–microtubule interfaces and process them into potentially antigenic peptides, thus reducing the load of aggregation-prone tau peptides. We term this mechanism the Proteostasis-Associated Immune Relay (PAIR), establishing I-PDBs as critical hubs linking proteostasis to immune surveillance with broad implications for disease. Graphical Abstract Highlights IFNγ drives BAG2-dependent Immune-Protein Degradation Bodies (I-PDBs) I-PDBs assemble at the endoplasmic reticulum and are enriched in immunoproteasome and MHC-I machinery I-PDBs shunt misfolded proteins, including pathological tau, away from aggresomes I-PDBs couple proteostasis to antigen presentation, enhancing CD8⁺ T cell recognition The Proteostasis-Associated Immune Relay (PAIR) defines a pathway linking proteostasis to adaptive immunity