BAG2 Condensates Couple Proteostasis to CD8+T Cell Surveillance

Almeida, M. C.; Wang, T.; Longhini, A. P.; Lobo, S.; Camargo, C. M.; Tinkle, E. D.; Kwon, M.; Duarte, G. Z.; Hirsch, I. O.; Ribeiro, C. A. J.; Ribeiro, F. A. O.; Shell, M. S.; Shea, J.-E.; Steen, J. A.; Kosik, K. S.; Carrettiero, D. C.

doi:10.64898/2026.04.24.719751

bioRxiv · 10.64898/2026.04.24.719751

BAG2 Condensates Couple Proteostasis to CD8+T Cell Surveillance

Almeida, M. C.·Wang, T.·Longhini, A. P.·Lobo, S.·Camargo, C. M.·Tinkle, E. D.·Kwon, M.·Duarte, G. Z.·Hirsch, I. O.·Ribeiro, C. A. J.·Ribeiro, F. A. O.·Shell, M. S.·Shea, J.-E.·Steen, J. A.·Kosik, K. S.·Carrettiero, D. C.

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Abstract

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. IFN{gamma} 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 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/719751v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@16fa503org.highwire.dtl.DTLVardef@ba7607org.highwire.dtl.DTLVardef@19ae5bdorg.highwire.dtl.DTLVardef@60fdf7_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIIFN{gamma} drives BAG2-dependent Immune-Protein Degradation Bodies (I-PDBs) C_LIO_LII-PDBs assemble at the endoplasmic reticulum and are enriched in immunoproteasome and MHC-I machinery C_LIO_LII-PDBs shunt misfolded proteins, including pathological tau, away from aggresomes C_LIO_LII-PDBs couple proteostasis to antigen presentation, enhancing CD8 T cell recognition C_LIO_LIThe Proteostasis-Associated Immune Relay (PAIR) defines a pathway linking proteostasis to adaptive immunity C_LI

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Almeida, M. C., Wang, T., Longhini, A. P., Lobo, S., Camargo, C. M., Tinkle, E. D., Kwon, M., Duarte, G. Z., Hirsch, I. O., Ribeiro, C. A. J., Ribeiro, F. A. O., Shell, M. S., Shea, J.-E., Steen, J. A., Kosik, K. S., Carrettiero, D. C.. 2026-04-27. BAG2 Condensates Couple Proteostasis to CD8+T Cell Surveillance. https://doi.org/10.64898/2026.04.24.719751

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