Co-chaperone BAG3 enters autophagic pathway via its interaction with microtubule associated protein 1 light chain 3 beta

Traffic. 2023 Dec;24(12):564-575. doi: 10.1111/tra.12916. Epub 2023 Sep 1.

Abstract

The co-chaperone BAG3 is a hub for a variety of cellular pathways via its multiple domains and its interaction with chaperones of the HSP70 family or small HSPs. During aging and under cellular stress conditions in particular, BAG3, together with molecular chaperones, ensures the sequestration of aggregated or aggregation-prone ubiquitinated proteins to the autophagic-lysosomal system via ubiquitin receptors. Accumulating evidence for BAG3-mediated selective autophagy independent of cargo ubiquitination led to analyses predicting a direct interaction of BAG3 with LC3 proteins. Phylogenetically, BAG3 comprises several highly conserved potential LIRs, LC3-interacting regions, which might allow for the direct targeting of BAG3 including its cargo to autophagosomes and drive their autophagic degradation. Based on pull-down experiments, peptide arrays and proximity ligation assays, our results provide evidence of an interaction of BAG3 with LC3B. In addition, we could demonstrate that disabling all predicted LIRs abolished the inducibility of a colocalization of BAG3 with LC3B-positive structures and resulted in a substantial decrease of BAG3 levels within purified native autophagic vesicles compared with wild-type BAG3. These results suggest an autophagic targeting of BAG3 via interaction with LC3B. Therefore, we conclude that, in addition to being a key co-chaperone to HSP70, BAG3 may also act as a cargo receptor for client proteins, which would significantly extend the role of BAG3 in selective macroautophagy and protein quality control.

Keywords: BAG3; BAG3-mediated autophagy; Bcl2-associated athanogene 3; LC3; LIR.

MeSH terms

  • Adaptor Proteins, Signal Transducing* / metabolism
  • Apoptosis Regulatory Proteins* / metabolism
  • Autophagy
  • Carrier Proteins
  • HSP70 Heat-Shock Proteins / metabolism
  • Humans
  • Microtubule-Associated Proteins / metabolism
  • Molecular Chaperones / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • Molecular Chaperones
  • Microtubule-Associated Proteins
  • HSP70 Heat-Shock Proteins
  • Carrier Proteins
  • BAG3 protein, human