HSPB8 frameshift mutant aggregates weaken chaperone-assisted selective autophagy in neuromyopathies
Articolo
Data di Pubblicazione:
2023
Citazione:
HSPB8 frameshift mutant aggregates weaken chaperone-assisted selective autophagy in neuromyopathies / B. Tedesco, L. Vendredy, E. Adriaenssens, M. Cozzi, B. Asselbergh, V. Crippa, R. Cristofani, P. Rusmini, V. Ferrari, E. Casarotto, M. Chierichetti, F. Mina, P. Pramaggiore, M. Galbiati, M. Piccolella, J. Baets, F. Baeke, R. De Rycke, V. Mouly, T. Laurenzi, I. Eberini, A. Vihola, B. Udd, L. Weiss, V. Kimonis, V. Timmerman, A. Poletti. - In: AUTOPHAGY. - ISSN 1554-8627. - (2023), pp. 1-23. [Epub ahead of print] [10.1080/15548627.2023.2179780]
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.Abbreviations : ACD: α-crystallin domain; ACTN: actinin alpha; BAG3: BAG cochaperone 3; C: carboxy; CASA: chaperone-assisted selective autophagy; CE: carboxy-terminal extension; CLEM: correlative light and electron microscopy; CMT2L: Charcot-Marie-Tooth type 2L; CTR: carboxy-terminal region; dHMNII: distal hereditary motor neuropathy type II; EV: empty vector; FRA: filter retardation assay; fs: frameshift; HSPA/HSP70: heat shock protein family A (Hsp70); HSPB1/Hsp27: heat shock protein family B (small) member 1; HSPB8/Hsp22: heat shock protein family B (small) member 8; HTT: huntingtin; KO: knockout; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MD: molecular dynamics; MTOC: microtubule organizing center; MYH: myosin heavy chain; MYOG: myogenin; NBR1: NBR1 autophagy cargo receptor; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; NSC34: Neuroblastoma X Spinal Cord 34; OPTN: optineurin; polyQ: polyglutamine; SQSTM1/p62: sequestosome 1; STUB1/CHIP: STIP1 homology and U-box containing protein 1; TARDBP/TDP-43: TAR DNA binding protein; TAX1BP1: Tax1 binding protein 1; TUBA: tubulin alpha; WT: wild-type.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
BAG3; CASA; HSPA; HSPB8; misfolding; myopathy; neuromuscular disorders; neuropathy; protein quality control
Elenco autori:
B. Tedesco, L. Vendredy, E. Adriaenssens, M. Cozzi, B. Asselbergh, V. Crippa, R. Cristofani, P. Rusmini, V. Ferrari, E. Casarotto, M. Chierichetti, F. Mina, P. Pramaggiore, M. Galbiati, M. Piccolella, J. Baets, F. Baeke, R. De Rycke, V. Mouly, T. Laurenzi, I. Eberini, A. Vihola, B. Udd, L. Weiss, V. Kimonis, V. Timmerman, A. Poletti
Link alla scheda completa: