BAG3: a multifaceted protein that regulates major cell pathways

Rosati, A; Graziano, V; De Laurenzi, V; Pascale, M; Turco, M C

The role played by BAG3 in the cytoskeleton remodeling and membrane trafficking suggests the possibility that it might be involved in autophagy. With this term, we refer to a set of nonspecific bulk degradation processes, in which cells deliver cytoplasmic substrates for lysosomal degradation. 69 There is a chaperone-mediated autophagy (CMA), selective for cytosolic proteins that contain a pentapeptide motif: this motif is recognized by the chaperone Hsc70, which transfers protein substrates to lysosomes. 69 As BAG3 is a Hsc/Hsp 70 co-chaperone, it is plausible to imagine its involvement in CMA, but we can also envisage a role in the other two types of autophagy, namely micro-and macroautophagy. In macroautophagy, cells form double-membrane vesicles, called autophagosomes, around a portion of cytoplasm; autophagosomes are trafficked along microtubules and fused with lysosomes, resulting in degradation of their contents. Microautophagy is a process in which lysosomes directly engulf cytoplasm. 69 Similar to Hsps and BAG3, autophagy is upregulated under stress. Indeed, the autophagic process is important in promoting cell survival in several conditions, such as protein aggregate formation, nutrient and growth factor deprivation, ER stress and pathogen infection. Defective autophagy is associated with diverse diseases, including neurodegeneration, lysosomal storage diseases, muscular dystrophies, cancers and Crohn's disease. 69 BAG3 participates, along with HspB8, a member of the HspB family of molecular chaperones, in the degradation of misfolded and aggregated proteins via macroautophagy. Indeed HspB8 forms a stable complex with BAG3 in cells and the formation of this complex is essential for the HspB8mediated degradation of the polyglutamine protein Htt43Q (HunTingTin exon 1 fragment with 43 CAG repeats), a pathogenic form of huntingtin prone to aggregation. 70, 71 HspB8 and BAG3 induce, in a Hsp70-independent manner, the phosphorylation of the a-subunit of the translation initiator factor eIF2; this in turn causes a translational shutdown and stimulates autophagy. The mechanism by which the BAG3/ HspB8 complex induces eIF2 phosphorylation is not completely understood. 70, 71 BAG3 binding to HspB8 is mediated by two conserved Ile-Pro-Val (IPV) motifs located between the W-and the Pro-rich domains of the co-chaperone; deletion of these motifs suppresses HspB8 activity in Htt43Q degradation. 72 Interestingly, the p.Pro209Leu mutation responsible for dystrophy is in one of the two IPV motifs. 58, 72 This suggests that the disease pathogenesis could involve defective autophagy. Through the same protein region, BAG3 can bind also to another chaperone HspB6. This is particularly intriguing in view of the cardioprotective property of HspB6/ Hsp20 73 and its role in myocyte contractility. 74 Finally, BAG3 complexes with the ubiquitin-binding protein p62/SQSTM1, that, by binding simultaneously the autophagosome protein LC3 and polyUb-proteins, controls the sequestration of polyUb-proteins into inclusion bodies for autophagic degradation. 75 Therefore, BAG3 appears to negatively regulate protein delivery to proteasome, by competing with BAG1, but at the same time it stimulates autophagy. This suggests that, although BAG1 constitutively assures, in combination with Hsc/Hsp70, proteostasis through the ubiquitin-proteasome system (UPS), stressful stimuli, by inducing BAG3 increase, determine an inhibition of UPS (because of the BAG3 competition with