BAG2 Condensates Couple Proteostasis to CD8 + T Cell Surveillance

Protein aggregation, impaired degradation, and immune activation are central hallmarks of many neurodegenerative diseases, yet how these processes are coordinated remain unclear. Here we identify a new class of phase-separated proteostasis organelles, termed immune degradation condensates (IDCs), composed of BAG2 assemblies. Inflammatory cues drive the formation of BAG2 IDCs, which are enriched in immunoproteasome components, major histocompatibility complex class I (MHC-I) peptide-loading machinery, and chaperones associated with the endoplasmic reticulum (ER). These assemblies redirect proteostatic cargo from centrosomal aggregation pathways to immune-specialized sites, coupling substrate clearance to antigenic peptide production and enhancing CD8⁺ T cell engagement. Using a cellular model of aggregation-prone Tau, we show that BAG2 IDCs capture pathological Tau fibrils at ER–microtubule interfaces and process them into antigenic peptides, thereby reducing the abundance of the aggregation-prone PHF6 motif. We term this system the Proteostasis-Associated Immune Relay (PAIR), establishing IDCs as critical hubs with potential implications for multiple disease states.