BAG3 Pro209 mutants associated with myopathy and neuropathy relocate chaperones of the CASA-complex to aggresomes

Abstract

Three missense mutations targeting the same proline 209 (Pro209) codon in the co-chaperone Bcl2-associated athanogene 3 (BAG3) have been reported to cause distal myopathy, dilated cardiomyopathy or Charcot-Marie-Tooth type 2 neuropathy. Yet, it is unclear whether distinct molecular mechanisms underlie the variable clinical spectrum of the rare patients carrying these three heterozygous Pro209 mutations in BAG3. Here, we studied all three variants and compared them to the BAG3_Glu455Lys mutant, which causes dilated cardiomyopathy. We found that all BAG3_Pro209 mutants have acquired a toxic gain-of-function, which causes these variants to accumulate in the form of insoluble HDAC6-and vimentin-positive aggresomes. The aggresomes formed by mutant BAG3 sequestered other chaperones such as HSPB8 and Hsp70, which, together with BAG3, promote the so called chaperone-assisted selective autophagy (CASA). As a consequence of their increased aggregation-proneness, mutant BAG3 trapped ubiquitinylated client proteins at the aggresome, preventing their efficient clearance. Combined, these data show that all BAG3_Pro209 mutants, irrespective of their different clinical phenotypes, are characterized by a gain-of-function that contributes to the gradual loss of protein homeostasis.

Cardiomyocyte Contractile Impairment in Heart Failure Results from Reduced BAG3-mediated Sarcomeric Protein Turnover

“…These chaperones have roles in protein folding, stabilization, 29 and degradation and are essential for sarcomere protein turnover 10 . The importance of 30 maintaining sarcomere proteostasis in cardiomyocytes is accentuated by the fact that these 31 cells are terminally differentiated and must survive for many years throughout which they 32 experience constant mechanical stress. However, despite its evident importance, there is little 33 mechanistic understanding of sarcomeric protein quality control.…”