BAG3 plays a central role in proteostasis in the heart
Wataru Mizushima, Junichi Sadoshima
Wataru Mizushima, Junichi Sadoshima
Published August 1, 2017; First published July 24, 2017
Citation Information: J Clin Invest. 2017;127(8):2900-2903. https://doi.org/10.1172/JCI95839.
View: Text | PDF
Category: Commentary

BAG3 plays a central role in proteostasis in the heart

Abstract

Proteinopathies are characterized by the accumulation of misfolded proteins, which ultimately interfere with normal cell function. While neurological diseases, such as Huntington disease and Alzheimer disease, are well-characterized proteinopathies, cardiac diseases have recently been associated with alterations in proteostasis. In this issue of the JCI, Fang and colleagues demonstrate that mice with cardiac-specific deficiency of the co-chaperone protein BCL2-associated athanogene 3 (BAG3) develop dilated cardiomyopathy that is associated with a destabilization of small HSPs as the result of a disrupted interaction between BAG3 and HSP70. Together, the results of this study suggest that strategies to upregulate BAG3 during cardiac dysfunction may be beneficial.

Authors

Wataru Mizushima, Junichi Sadoshima

×

Figure 1

Putative functions of BAG3 in the heart and the underlying mechanisms of cardiomyopathy caused by loss of BAG3 function.

Options: View larger image (or click on image) Download as PowerPoint
Putative functions of BAG3 in the heart and the underlying mechanisms of...
BAG3 plays a critical role in the PQC system in the heart. WT BAG3 forms multi-chaperone complexes with HSP70/HSC70 and sHSPs via its IPV motif and BAG3 domain. The BAG3-HSPB8-HSC70 complex binds to misfolded proteins and either promotes refolding or degradation of these misfolded proteins. Degradation is mediated primarily through general autophagy. The BAG3-HSPB8-HSC70 complex also maintains the structure and integrity of sarcomeres via CASA, a substrate-specific form of autophagy. In addition, BAG3 binds to dynein via the proline-rich motif (PXXP) and segregates misfolded proteins into aggresomes located in the perinuclear space through retrograde transport. The BAG3E455K mutation, which is located in the middle of the BAG domain, attenuates the interaction between BAG3 and HSP70/HSC70, leading to destabilization of sHSPs, including HSPB8. This disturbance of the chaperone complexes induces dysregulation of the refolding and degradation processes (autophagy and CASA), resulting in accumulation of BAG3 complex substrate proteins involved in metabolism and cardiac contraction in the detergent-insoluble fraction. Interestingly, aggresomes are not obvious in the BAG3 loss-of-function mouse model, possibly because of the defect in retrograde transport. Despite the absence of large protein aggregates, BAG3 loss-of-function mice develop DCM.