Inhibition of DNAJ-HSP70 interaction improves strength in muscular dystrophy

Bengoechea, Rocío; Findlay, Andrew; Bhadra, Ankan Kumar; Shao, Hao; Stein, Kevin C.; Pittman, Sara K.; Daw, Jil; Gestwicki, Jason E.; True, Heather L.; Weihl, Conrad C.

doi:10.1172/jci136167

Cited by 22 publications

(52 citation statements)

References 35 publications

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“…Another study on chaperone regulation found that the underlying mechanism of the inherited muscular dystrophy disease LGMD1D is due to increased affinity between HSP70 and a mutated variant of the JDP DNAJB6, thereby locking HSP70 to this complex, preventing it from completing its cellular tasks. By inhibiting the interaction between HSP70 and DNAJB6, HSP70 molecules were released, relieving disease models from symptoms of muscular dystrophy [166].…”

Section: Regulation Of Chaperone Activitymentioning

confidence: 99%

Co-Chaperones in Targeting and Delivery of Misfolded Proteins to the 26S Proteasome

et al. 2020

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Protein homeostasis (proteostasis) is essential for the cell and is maintained by a highly conserved protein quality control (PQC) system, which triages newly synthesized, mislocalized and misfolded proteins. The ubiquitin-proteasome system (UPS), molecular chaperones, and co-chaperones are vital PQC elements that work together to facilitate degradation of misfolded and toxic protein species through the 26S proteasome. However, the underlying mechanisms are complex and remain partly unclear. Here, we provide an overview of the current knowledge on the co-chaperones that directly take part in targeting and delivery of PQC substrates for degradation. While J-domain proteins (JDPs) target substrates for the heat shock protein 70 (HSP70) chaperones, nucleotide-exchange factors (NEFs) deliver HSP70-bound substrates to the proteasome. So far, three NEFs have been established in proteasomal delivery: HSP110 and the ubiquitin-like (UBL) domain proteins BAG-1 and BAG-6, the latter acting as a chaperone itself and carrying its substrates directly to the proteasome. A better understanding of the individual delivery pathways will improve our ability to regulate the triage, and thus regulate the fate of aberrant proteins involved in cell stress and disease, examples of which are given throughout the review.

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Section: Regulation Of Chaperone Activitymentioning

confidence: 99%

Co-Chaperones in Targeting and Delivery of Misfolded Proteins to the 26S Proteasome

et al. 2020

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“…A key function for Hsp40s is stimulating Hsp70s. Based on our previous work, we hypothesized that the deleterious effect of the DNAJB6 G/F domain mutants is HSP70-dependent 31 . Thus, the LGMDD1 mutants might be altered in their productive association with Hsp70.…”

Section: Resultsmentioning

confidence: 99%

Myopathy mutations in DNAJB6 slow conformer specific substrate processing that is corrected by NEF modulation

Bhadra

Rau

Daw

et al. 2021

Preprint

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Molecular chaperones, or heat shock proteins (HSPs), protect against the toxic misfolding and aggregation of proteins. As such, mutations or deficiencies within the chaperone network can lead to disease. In fact, dominant mutations in DNAJB6 (Hsp40/Sis1), an Hsp70 co-chaperone, leads to a protein aggregate myopathy termed Limb-Girdle Muscular Dystrophy Type D1 (LGMDD1). DNAJB6 client proteins and co-chaperone interactions in skeletal muscle are not known. Here, we used the yeast prion model client in conjunction with in vitro chaperone activity assays to gain mechanistic insights, and found that LGMDD1 mutants affect Hsp40 functions. Strikingly, the mutants changed the structure of client protein aggregates, as determined by altered distribution of prion strains. They also impair the Hsp70 ATPase cycle, dimerization, and substrate processing and consequently poison the function of wild-type protein. These results define the mechanisms by which LGMDD1 mutations alter chaperone activity and provide avenues for therapeutic intervention.

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“…To date, all reported myopathic mutations have been located in exons 4 and 5, which affect both isoforms of DNAJB6 [ 8 , 17 , 18 , 22 , 28 , 30 , 31 , 35 , 37 , 39 , 45 ]. A recent study showed that LGMD D1 mutations in DNAJB6 have a dominant gain-of-function effect on protein quality control and myopathic phenotypes, which can be partially corrected by inhibiting the DNAJB6–HSP70 interaction in both yeast and mouse models [ 3 ]. However, DNAJB6b-F93L overexpressing mice exhibit obvious myopathic features compared to DNAJB6a-F93L overexpressing mice, which indicated that the DNAJB6b-mutant isoform was the pathogenic driver of myopathy [ 4 ].…”

Section: Discussionmentioning

confidence: 99%

“…18-month-old HOM mice displayed severe myofiber disruption (black arrowheads, 4) and vacuolated mitochondria (black asterisk, 4). Scale bars = 0.5 µm (1,3,4)…”

Section: Muscle Fiber Type Composition In Dnajb6 Ki Micementioning

confidence: 99%

A novel recessive mutation affecting DNAJB6a causes myofibrillar myopathy

Qian

Guo

et al. 2021

acta neuropathol commun

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Mutations in the DNAJB6 gene have been identified as rare causes of myofibrillar myopathies. However, the underlying pathophysiologica mechanisms remain elusive. DNAJB6 has two known isoforms, including the nuclear isoform DNAJB6a and the cytoplasmic isoform DNAJB6b, which was thought to be the pathogenic isoform. Here, we report a novel recessive mutation c.695_699del (p. Val 232 Gly fs*7) in the DNAJB6 gene, associated with an apparently recessively inherited late onset distal myofibrillar myopathy in a Chinese family. Notably, the novel mutation localizes to exon 9 and uniquely encodes DNAJB6a. We further identified that this mutation decreases the mRNA and protein levels of DNAJB6a and results in an age-dependent recessive toxic effect on skeletal muscle in knock-in mice. Moreover, the mutant DNAJB6a showed a dose-dependent anti-aggregation effect on polyglutamine-containing proteins in vitro. Taking together, these findings reveal the pathogenic role of DNAJB6a insufficiency in myofibrillar myopathies and expand upon the molecular spectrum of DNAJB6 mutations.

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Inhibition of DNAJ-HSP70 interaction improves strength in muscular dystrophy

Cited by 22 publications

References 35 publications

Co-Chaperones in Targeting and Delivery of Misfolded Proteins to the 26S Proteasome

Co-Chaperones in Targeting and Delivery of Misfolded Proteins to the 26S Proteasome

Myopathy mutations in DNAJB6 slow conformer specific substrate processing that is corrected by NEF modulation

A novel recessive mutation affecting DNAJB6a causes myofibrillar myopathy

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