The chaperone-autophagy coupling hypothesis centers on the critical interaction between p62/SQSTM1 and the heat shock protein 70 (HSP70) chaperone system to prevent pathological protein aggregation through enhanced autophagic clearance via chaperone-assisted selective autophagy (CASA). Unlike proteasomal degradation, this mechanism targets larger protein complexes and early aggregation intermediates that exceed the size limitations of the 26S proteasome pore. The process involves p62's multidomain architecture: an N-terminal Phox and Bem1 (PB1) domain enabling oligomerization, a central LC3-interacting region (LIR) that binds LC3/GABARAP family proteins, and a C-terminal ubiquitin-associated (UBA) domain that recognizes polyubiquitinated substrates. When misfolded proteins such as tau or α-synuclein bind to HSP70, the chaperone-substrate complex is recognized by BAG3 (Bcl2-associated athanogene 3), which preferentially directs substrates toward autophagy rather than proteasomal degradation. BAG3's WW domain interacts with proline-rich regions in p62, creating a molecular bridge between the chaperone machinery and the autophagy system.

The chaperone-autophagy coupling hypothesis centers on the critical interaction between p62/SQSTM1 and the heat shock protein 70 (HSP70) chaperone system to prevent pathological protein aggregation through enhanced autophagic clearance via chaperone-assisted selective autophagy (CASA). Unlike proteasomal degradation, this mechanism targets larger protein complexes and early aggregation intermediates that exceed the size limitations of the 26S proteasome pore. The process involves p62's multidomain architecture: an N-terminal Phox and Bem1 (PB1) domain enabling oligomerization, a central LC3-interacting region (LIR) that binds LC3/GABARAP family proteins, and a C-terminal ubiquitin-associated (UBA) domain that recognizes polyubiquitinated substrates. When misfolded proteins such as tau or α-synuclein bind to HSP70, the chaperone-substrate complex is recognized by BAG3 (Bcl2-associated athanogene 3), which preferentially directs substrates toward autophagy rather than proteasomal degradation. BAG3's WW domain interacts with proline-rich regions in p62, creating a molecular bridge between the chaperone machinery and the autophagy system. This interaction is enhanced by p62 phosphorylation at Ser403 by ULK1 kinase, which increases its affinity for polyubiquitinated cargo and promotes the formation of sequestosomes - membrane-less organelles that concentrate misfolded proteins for autophagic clearance. The specificity of this pathway is regulated by the HSP70 co-chaperone ratio: high BAG3/BAG1 ratios favor autophagy over proteasomal degradation, particularly under stress conditions or in post-mitotic cells with limited proteasome capacity. This mechanism is especially critical for clearing large oligomeric species and fibrillar intermediates that serve as seeding templates for pathological aggregation, effectively breaking the propagation cycle of protein misfolding diseases through selective removal of the most toxic conformational variants.