BAG5 Promotes Alpha-Synuclein Oligomer Formation and Functionally Interacts With the Autophagy Adaptor Protein p62

Abstract

Molecular chaperones are critical to maintaining intracellular proteostasis and have been shown to have a protective role against alpha-synuclein-mediated toxicity. Cochaperone proteins regulate the activity of molecular chaperones and connect the chaperone network to protein degradation and cell death pathways. Bcl-2 associated athanogene 5 (BAG5) is a co-chaperone that modulates proteostasis by inhibiting the activity of Heat shock protein 70 (Hsp70) and several E3 ubiquitin ligases, resulting in enhanced neurodegeneration in models of Parkinson's disease (PD). Here we identify a novel interaction between BAG5 and p62/sequestosome-1 (SQSTM1), suggesting that BAG5 may bridge the chaperone network to autophagy-mediated protein degradation. We found that BAG5 enhanced the formation of pathogenic alpha-synuclein oligomers and regulated the levels and subcellular distribution of p62. These results extend the role of BAG5 in alpha-synuclein processing and intracellular proteostasis.

On the origin of BAG(3) and its consequences for an expansion of BAG3's role in protein homeostasis

“…Members of the B‐cell CLL 2‐associated athanogene (BAG) protein family are major regulators of cellular proteostasis 4–7 . Most vertebrates evolved six different paralogues of the BAG family (BAG1–6), all of which have at least one C‐terminal BAG domain.…”

“…Members of the B-cell CLL 2-associated athanogene (BAG) protein family are major regulators of cellular proteostasis. [4][5][6][7] Most vertebrates evolved six different paralogues of the BAG family (BAG1-6), all of which have at least one C-terminal BAG domain. This domain allows the proteins to act as cochaperone to the chaperones 70-kDa heat shock protein and heat shock cognate 71-kDa protein.…”

BAG Family Members as Mitophagy Regulators in Mammals

“…Indeed, BAG5 knock-down reduces P62 protein levels and promotes the formation of alpha-synuclein oligomers. Although the molecular mechanism underlying this interaction remains to be elucidated, BAG5 may promote aggrephagy, which plays a role in PD pathogenesis [ 40 ].…”

“…The first evidence of BAG6’s role in autophagy came from the observation that it can modulate the activity of the acetyltransferase EP300 [ 40 , 41 ]. Indeed, BAG6 regulates autophagy by acting as a nucleocytoplasmic vehicle for EP300, thus controlling its localization and accessibility to nuclear (P53) and cytoplasmic (ATG proteins) substrates involved in autophagy [ 42 , 43 ].…”

Role of BAG5 in Protein Quality Control: Double-Edged Sword?

“…Molecular chaperones are the class of proteins that create equilibrium between protein synthesis and degradation in the cell ( Arakawa et al, 2010 ; Friesen et al, 2020 ). The molecular chaperones and co-chaperones participate in enhancing protein refolding and protecting cells against the buildup of misfolded proteins ( Arakawa et al, 2010 ; Friesen et al, 2020 ).…”