Abstract
The BCL-2-associated athanogene (BAG) family is a multifunctional group of co-chaperones that are evolutionarily conserved from yeast to mammals. In addition to their common BAG domain, these proteins contain, in their sequences, many specific domains/motifs required for their various functions in cellular quality control, such as autophagy, apoptosis, and proteasomal degradation of misfolded proteins. The BAG family includes six members (BAG1 to BAG6). Recent studies reported their roles in autophagy and/or mitophagy through interaction with the autophagic machinery (LC3, Beclin 1, P62) or with the PINK1/Parkin signaling pathway. This review describes the mechanisms underlying BAG family member functions in autophagy and mitophagy and the consequences in physiopathology.
Highlights
The maintenance of cellular homeostasis depends on the tight equilibrium between anabolism and catabolism
Six functional groups are involved in the autophagic process: (1) the initiation complex, which requires the inhibition of the kinase mTOR and contains the ULK1 (ATG1) kinase and ATG13, among others; (2) the nucleation complex with phosphatidylintol 3-kinase class III (PI3KIII) and Beclin1 (ATG6); (3) the ATG12-ATG5-ATG16L elongation complex; (4) the protein light chain 3 (LC3) family/phosphatidylethanolamine elongation/conjugation system [3]; (5) the autophagosome/lysosome fusion complex composed of Rab GTPases, soluble NSF (Nethylmaleimide-sensitive factor) attachment protein receptor (SNARE), homotypic fusion and protein sorting (HOPS), and Pleckstrin homology domain-containing family member 1 (PLEKHM1); and (6) the efflux machinery to allow the recycling of nutrients (Figure 1)
BAG2, BAG3, and BAG5 interact with P62
Summary
The maintenance of cellular homeostasis depends on the tight equilibrium between anabolism and catabolism. If autophagy represents one of the main mechanisms for the maintenance of cellular homeostasis, another critical point of control concerns protein quality control, called proteostasis This mechanism requires the triage of misfolded proteins that will undergo refolding or degradation through the proteasome or the chaperone-mediated autophagy pathway to avoid protein aggregation, for example. During ER stress, BAG6 is cleaved by caspase 3, leading to its cytoplasmic localization and its interaction with pro-LC3 and LC3-I via the LIR motif (LIR132−135) In this case, BAG6 sequesters LC3-I, preventing autophagosome formation and promoting apoptosis [44]. Role in Autophagy Modulation of autophagy in function of its intracellular localization [42,43]: - In the cytoplasm at basal level: BAG6 sequesters EP300 in the cytoplasm and promotes EP300 dependent acetylation of ATG 1. Inhibition of autophagy: After its cleavage, BAG6 sequesters LC3-I leading to autophagy inhibition [44]
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