BAG3 Pro209 mutants associated with myopathy and neuropathy relocate chaperones of the CASA-complex to aggresomes.
Sci Rep
; 10(1): 8755, 2020 05 29.
Article
en En
| MEDLINE
| ID: mdl-32472079
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 led to a relocation of 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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Cardiomiopatía Dilatada
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Enfermedad de Charcot-Marie-Tooth
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Chaperonas Moleculares
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Mutación Missense
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Miopatías Distales
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Proteínas Adaptadoras Transductoras de Señales
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Proteínas Reguladoras de la Apoptosis
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Agregación Patológica de Proteínas
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Agregado de Proteínas
Tipo de estudio:
Risk_factors_studies
Límite:
Humans
Idioma:
En
Revista:
Sci Rep
Año:
2020
Tipo del documento:
Article
País de afiliación:
Bélgica