CHIP-mediated K63-linked ubiquitination promotes autophagosomal sequestration of pathologic oligomers through p62/SQSTM1 recruitment

The carboxy terminus of Hsc70-interacting protein (CHIP, encoded by STUB1) functions as a dual-specificity E3 ubiquitin ligase that selectively targets pathological protein oligomers for autophagic degradation rather than proteasomal processing. CHIP's TPR domain recognizes HSP70-bound oligomeric substrates through the same conformational sensing mechanism, but the degradation pathway diverges based on the specific E2 ubiquitin-conjugating enzyme recruited. When CHIP associates with UBE2N (Ubc13), it catalyzes K63-linked polyubiquitination of pathological oligomers, creating a distinct ubiquitin signal that is recognized by the autophagy receptor p62/SQSTM1 rather than proteasomal machinery. The K63-linked chains serve as molecular platforms for p62 oligomerization through its UBA domain, while p62's LIR motif simultaneously binds LC3/GABARAP on autophagosome membranes. This creates a bridging complex that sequesters CHIP-tagged oligomers within autophagosomes for lysosomal degradation. VCP facilitates this process by extracting K63-ubiquitinated substrates from CHIP-HSP70 complexes and concentrating them at p62-positive protein aggregation sites.

The carboxy terminus of Hsc70-interacting protein (CHIP, encoded by STUB1) functions as a dual-specificity E3 ubiquitin ligase that selectively targets pathological protein oligomers for autophagic degradation rather than proteasomal processing. CHIP's TPR domain recognizes HSP70-bound oligomeric substrates through the same conformational sensing mechanism, but the degradation pathway diverges based on the specific E2 ubiquitin-conjugating enzyme recruited. When CHIP associates with UBE2N (Ubc13), it catalyzes K63-linked polyubiquitination of pathological oligomers, creating a distinct ubiquitin signal that is recognized by the autophagy receptor p62/SQSTM1 rather than proteasomal machinery. The K63-linked chains serve as molecular platforms for p62 oligomerization through its UBA domain, while p62's LIR motif simultaneously binds LC3/GABARAP on autophagosome membranes. This creates a bridging complex that sequesters CHIP-tagged oligomers within autophagosomes for lysosomal degradation. VCP facilitates this process by extracting K63-ubiquitinated substrates from CHIP-HSP70 complexes and concentrating them at p62-positive protein aggregation sites. The specificity for oligomeric versus monomeric proteins arises from the increased avidity of multiple K63-ubiquitin chains present on oligomers, which exceeds the binding threshold required for stable p62 recruitment and autophagosome formation. BECN1 and ATG7 are essential cofactors that regulate autophagosome biogenesis in response to CHIP-generated ubiquitin signals, with ATG7 catalyzing LC3 lipidation necessary for autophagosome closure around sequestered oligomers.