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HSPB8 frameshift mutant aggregates weaken chaperone-assisted selective autophagy in neuromyopathies

Barbara Tedesco, Leen Vendredy, Elias Adriaenssens, Marta Cozzi, Bob Asselbergh, Valeria Crippa, Riccardo Cristofani, Paola Rusmini, Veronica Ferrari, Elena Casarotto, et al.
(2023) AUTOPHAGY. 19(8). p.2217-2239
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Abstract
Chaperone-assisted selective autophagy (CASA) is a highly selective pathway for the disposal of misfolding and aggregating proteins. In muscle, CASA assures muscle integrity by favoring the turnover of structural components damaged by mechanical strain. In neurons, CASA promotes the removal of aggregating substrates. A crucial player of CASA is HSPB8 (heat shock protein family B (small) member 8), which acts in a complex with HSPA, their cochaperone BAG3, and the E3 ubiquitin ligase STUB1. Recently, four novel HSPB8 frameshift (fs) gene mutations have been linked to neuromyopathies, and encode carboxy-terminally mutated HSPB8, sharing a common C-terminal extension. Here, we analyzed the biochemical and functional alterations associated with the HSPB8_fs mutant proteins. We demonstrated that HSPB8_fs mutants are highly insoluble and tend to form proteinaceous aggregates in the cytoplasm. Notably, all HSPB8 frameshift mutants retain their ability to interact with CASA members but sequester them into the HSPB8-positive aggregates together with two autophagy receptors SQSTM1/p62 and TAX1BP1. This copartitioning process negatively affects the CASA capability to remove its clients and causes a general failure in proteostasis response. Further analyses revealed that the aggregation of the HSPB8_fs mutants occurs independently of the other CASA members or from the autophagy receptors interaction, but it is an intrinsic feature of the mutated amino acid sequence. HSPB8_fs mutants aggregation alters the differentiation capacity of muscle cells and impairs sarcomere organization. Collectively, these results shed light on a potential pathogenic mechanism shared by the HSPB8_fs mutants described in neuromuscular diseases.
Keywords
BAG3, CASA, HSPA, HSPB8, misfolding, myopathy, neuromuscular disorders, neuropathy, protein quality control, HEAT-SHOCK-PROTEIN, ALPHA-B-CRYSTALLIN, TARGETING MISFOLDED PROTEINS, HEREDITARY MOTOR NEUROPATHY, MYOPATHY, MUTATIONS, CARDIOMYOPATHY, ASSOCIATION, PHENOTYPE

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MLA
Tedesco, Barbara, et al. “HSPB8 Frameshift Mutant Aggregates Weaken Chaperone-Assisted Selective Autophagy in Neuromyopathies.” AUTOPHAGY, vol. 19, no. 8, 2023, pp. 2217–39, doi:10.1080/15548627.2023.2179780.
APA
Tedesco, B., Vendredy, L., Adriaenssens, E., Cozzi, M., Asselbergh, B., Crippa, V., … Poletti, A. (2023). HSPB8 frameshift mutant aggregates weaken chaperone-assisted selective autophagy in neuromyopathies. AUTOPHAGY, 19(8), 2217–2239. https://doi.org/10.1080/15548627.2023.2179780
Chicago author-date
Tedesco, Barbara, Leen Vendredy, Elias Adriaenssens, Marta Cozzi, Bob Asselbergh, Valeria Crippa, Riccardo Cristofani, et al. 2023. “HSPB8 Frameshift Mutant Aggregates Weaken Chaperone-Assisted Selective Autophagy in Neuromyopathies.” AUTOPHAGY 19 (8): 2217–39. https://doi.org/10.1080/15548627.2023.2179780.
Chicago author-date (all authors)
Tedesco, Barbara, Leen Vendredy, Elias Adriaenssens, Marta Cozzi, Bob Asselbergh, Valeria Crippa, Riccardo Cristofani, Paola Rusmini, Veronica Ferrari, Elena Casarotto, Marta Chierichetti, Francesco Mina, Paola Pramaggiore, Mariarita Galbiati, Margherita Piccolella, Jonathan Baets, Femke Baeke, Riet De Rycke, Vincent Mouly, Tommaso Laurenzi, Ivano Eberini, Anna Vihola, Bjarne Udd, Lan Weiss, Virginia Kimonis, Vincent Timmerman, and Angelo Poletti. 2023. “HSPB8 Frameshift Mutant Aggregates Weaken Chaperone-Assisted Selective Autophagy in Neuromyopathies.” AUTOPHAGY 19 (8): 2217–2239. doi:10.1080/15548627.2023.2179780.
Vancouver
1.
Tedesco B, Vendredy L, Adriaenssens E, Cozzi M, Asselbergh B, Crippa V, et al. HSPB8 frameshift mutant aggregates weaken chaperone-assisted selective autophagy in neuromyopathies. AUTOPHAGY. 2023;19(8):2217–39.
IEEE
[1]
B. Tedesco et al., “HSPB8 frameshift mutant aggregates weaken chaperone-assisted selective autophagy in neuromyopathies,” AUTOPHAGY, vol. 19, no. 8, pp. 2217–2239, 2023.
@article{01H7AVEYRPZR5D5Z3PV7P63H6S,
  abstract     = {{Chaperone-assisted selective autophagy (CASA) is a highly selective pathway for the disposal of misfolding and aggregating proteins. In muscle, CASA assures muscle integrity by favoring the turnover of structural components damaged by mechanical strain. In neurons, CASA promotes the removal of aggregating substrates. A crucial player of CASA is HSPB8 (heat shock protein family B (small) member 8), which acts in a complex with HSPA, their cochaperone BAG3, and the E3 ubiquitin ligase STUB1. Recently, four novel HSPB8 frameshift (fs) gene mutations have been linked to neuromyopathies, and encode carboxy-terminally mutated HSPB8, sharing a common C-terminal extension. Here, we analyzed the biochemical and functional alterations associated with the HSPB8_fs mutant proteins. We demonstrated that HSPB8_fs mutants are highly insoluble and tend to form proteinaceous aggregates in the cytoplasm. Notably, all HSPB8 frameshift mutants retain their ability to interact with CASA members but sequester them into the HSPB8-positive aggregates together with two autophagy receptors SQSTM1/p62 and TAX1BP1. This copartitioning process negatively affects the CASA capability to remove its clients and causes a general failure in proteostasis response. Further analyses revealed that the aggregation of the HSPB8_fs mutants occurs independently of the other CASA members or from the autophagy receptors interaction, but it is an intrinsic feature of the mutated amino acid sequence. HSPB8_fs mutants aggregation alters the differentiation capacity of muscle cells and impairs sarcomere organization. Collectively, these results shed light on a potential pathogenic mechanism shared by the HSPB8_fs mutants described in neuromuscular diseases.}},
  author       = {{Tedesco, Barbara and Vendredy, Leen and  Adriaenssens, Elias and  Cozzi, Marta and  Asselbergh, Bob and  Crippa, Valeria and  Cristofani, Riccardo and  Rusmini, Paola and  Ferrari, Veronica and  Casarotto, Elena and  Chierichetti, Marta and  Mina, Francesco and  Pramaggiore, Paola and  Galbiati, Mariarita and  Piccolella, Margherita and  Baets, Jonathan and Baeke, Femke and De Rycke, Riet and  Mouly, Vincent and  Laurenzi, Tommaso and  Eberini, Ivano and  Vihola, Anna and  Udd, Bjarne and  Weiss, Lan and  Kimonis, Virginia and Timmerman, Vincent and Poletti, Angelo}},
  issn         = {{1554-8627}},
  journal      = {{AUTOPHAGY}},
  keywords     = {{BAG3,CASA,HSPA,HSPB8,misfolding,myopathy,neuromuscular disorders,neuropathy,protein quality control,HEAT-SHOCK-PROTEIN,ALPHA-B-CRYSTALLIN,TARGETING MISFOLDED PROTEINS,HEREDITARY MOTOR NEUROPATHY,MYOPATHY,MUTATIONS,CARDIOMYOPATHY,ASSOCIATION,PHENOTYPE}},
  language     = {{eng}},
  number       = {{8}},
  pages        = {{2217--2239}},
  title        = {{HSPB8 frameshift mutant aggregates weaken chaperone-assisted selective autophagy in neuromyopathies}},
  url          = {{http://doi.org/10.1080/15548627.2023.2179780}},
  volume       = {{19}},
  year         = {{2023}},
}
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