Myopathy-causing Mutations in an HSP40 Chaperone Disrupt Processing of Specific Client Conformers

Stein, Kevin C.; Bengoechea, Rocío; Harms, Matthew B.; Weihl, Conrad C.; True, Heather L.

doi:10.1074/jbc.m114.572461

Cited by 53 publications

(107 citation statements)

References 48 publications

Supporting

Mentioning

103

Contrasting

Order By: Relevance

“…As we found previously, deletion of the G/F region eliminated the propagation of all five [ RNQ +] variants (Fig. C and Stein et al ., ). Interestingly, other than Sis1‐ΔG/F, both s.d.…”

Section: Resultsmentioning

confidence: 97%

“…Previous work has focused on the fact that different prions, or prion variants, show distinct sensitivity to chaperone levels (Fan et al ., ; Hines and Craig, ; Hines et al ., ). We have recently shown that the propagation of several different [ RNQ +] variants all require the presence of the Sis1 G/F region, while [ PSI +] variants show differential dependence on this region (Stein et al ., ). Here, we show that other domains of Sis1 are also important for substrate recognition or processing in a prion variant‐dependent manner.…”

Section: Discussionmentioning

confidence: 97%

“…WT yeast strains were kind gifts from S. Liebman (L1751, L1943, L1945, L1767 [ psi −], L1953, L1749, S12600, S12606) (Derkatch et al ., ; Bradley et al ., ; Bagriantsev and Liebman, ) and J. Weissman (2397, 2398) (Tanaka et al ., ). Construction of the sis1 Δ strains containing pRS316‐ SIS1 (see http://onlinelibrary.wiley.com/doi/10.1111/mmi.12725/suppinfo for plasmids used in this study) and the hsp104 Δ strains containing pRS316‐ HSP104p‐HSP104 were described previously (Dulle et al ., ; Stein et al ., ). To create the ssa2 Δ strains, the kanMX4 cassette having flanking homology to the SSA2 promoter and terminator was amplified from pFA6a using oligonucleotides 0978 and 0979 (see http://onlinelibrary.wiley.com/doi/10.1111/mmi.12725/suppinfo for oligonucleotides used in this study), followed by transforming yeast cells, and selecting for resistance to G418.…”

Section: Methodsmentioning

confidence: 97%

“…These regions are generally viewed as linker regions, but their function remains poorly understood. Interestingly, the G/F region is required for propagation of several different [ RNQ +] variants (Stein et al ., ). Propagation of [ PSI +] variants, on the other hand, differentially depends on this region (Stein et al ., ).…”

Section: Introductionmentioning

confidence: 97%

See 3 more Smart Citations

Structural variants of yeast prions show conformer‐specific requirements for chaperone activity

Stein

True

2014

Molecular Microbiology

Self Cite

View full text Add to dashboard Cite

Summary Molecular chaperones monitor protein homeostasis and defend against the misfolding and aggregation of proteins that is associated with protein conformational disorders. In these diseases, a variety of different aggregate structures can form. These are called prion strains, or variants, in prion diseases, and cause variation in disease pathogenesis. Here, we use variants of the yeast prions [RNQ+] and [PSI+] to explore the interactions of chaperones with distinct aggregate structures. We found that prion variants show striking variation in their relationship with Hsp40s. Specifically, the yeast Hsp40 Sis1, and its human ortholog Hdj1, had differential capacities to process prion variants, suggesting that Hsp40 selectivity has likely changed through evolution. We further show that such selectivity involves different domains of Sis1, with some prion conformers having a greater dependence on particular Hsp40 domains. Moreover, [PSI+] variants were more sensitive to certain alterations in Hsp70 activity as compared to [RNQ+] variants. Collectively, our data indicate that distinct chaperone machinery is required, or has differential capacity, to process different aggregate structures. Elucidating the intricacies of chaperone-client interactions, and how these are altered by particular client structures, will be crucial to understanding how this system can go awry in disease and contribute to pathological variation.

show abstract

“…As we found previously, deletion of the G/F region eliminated the propagation of all five [ RNQ +] variants (Fig. C and Stein et al ., ). Interestingly, other than Sis1‐ΔG/F, both s.d.…”

Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 97%

See 2 more Smart Citations

Structural variants of yeast prions show conformer‐specific requirements for chaperone activity

Stein

True

2014

Molecular Microbiology

Self Cite

View full text Add to dashboard Cite

show abstract

“…The Hsp70 recruitment ability of DNAJB6 was disrupted by replacing its J-domain HPD motif with an AAA sequence. DnaJB6 is mutated in inherited myofibrillar myopathy and limb-girdle muscular dystrophy (Stein et al, 2014), and we also tested the effect of a disease-linked DnaJB6b mutation on DENV replication (Fig. 6G, S5D, F93L).…”

Section: Resultsmentioning

confidence: 99%

Defining Hsp70 Subnetworks in Dengue Virus Replication Reveals Key Vulnerability in Flavivirus Infection

Taguwa

Maringer

et al. 2015

Cell

238

243

View full text Add to dashboard Cite

Summary Viral protein homeostasis depends entirely on the machinery of the infected cell. Accordingly, viruses can illuminate the interplay between cellular proteostasis components and their distinct substrates. Here we define how the Hsp70 chaperone network mediates the dengue virus life cycle. Cytosolic Hsp70 isoforms are required at distinct steps of the viral cycle, including entry, RNA replication and virion biogenesis. Hsp70 function at each step is specified by nine distinct DNAJ cofactors. Of these, DnaJB11 relocalizes to virus-induced replication complexes to promote RNA synthesis, while DnaJB6 associates with capsid protein and facilitates virion biogenesis. Importantly, an allosteric Hsp70 inhibitor, JG40, potently blocks infection of different dengue serotypes in human primary blood cells without eliciting viral resistance or exerting toxicity to the host cells. JG40 also blocks replication of other medically-important flaviviruses including yellow fever, West Nile and Japanese encephalitis viruses. Thus, targeting host Hsp70 subnetworks provides a path for broad-spectrum antivirals.

show abstract

LGMDD1 natural history and phenotypic spectrum: Implications for clinical trials

Findlay

Robinson

Poelker

et al. 2022

Ann Clin Transl Neurol

Self Cite

View full text Add to dashboard Cite

Objective To delineate the full phenotypic spectrum and characterize the natural history of limb girdle muscular dystrophy type D1 (LGMDD1). Methods We extracted age at clinical events of interest contributing to LGMDD1 disease burden via a systematic literature and chart review. Manual muscle testing and quantitative dynamometry data were used to estimate annualized rates of change. We also conducted a cross‐sectional observational study using previously validated patient‐reported outcome assessments (ACTIVLIM, PROMIS‐57) and a new LGMDD1 questionnaire. Some individuals underwent repeat ACTIVLIM and LGMDD1 questionnaire assessments at 1.5 and 2.5 years. Results A total of 122 LGMDD1 patients were included from 14 different countries. We identified two new variants (p.E54K, p.V99A). In vitro assays and segregation support their pathogenicity. The mean onset age was 29.7 years. Genotype appears to impact onset age, weakness pattern, and median time to loss of ambulation (34 years). Dysphagia was the most frequent abnormality (51.4%). Deltoids, biceps, grip, iliopsoas, and hamstrings strength decreased by (0.5‐1 lb/year). Cross‐sectional ACTIVLIM and LGMDD1 questionnaire scores correlated with years from disease onset. Longitudinally, only the LGMDD1 questionnaire detected significant progression at both 1.5 and 2.5 years. Treatment trials would require 62 (1.5 years) or 30 (2.5 years) patients to detect a 70% reduction in the progression of the LGMDD1 questionnaire. Interpretation This study is the largest description of LGMDD1 patients to date and highlights potential genotype‐dependent differences that need to be verified prospectively. Future clinical trials will need to account for variability in these key phenotypic features when selecting outcome measures and enrolling patients.

show abstract

Myopathy-causing Mutations in an HSP40 Chaperone Disrupt Processing of Specific Client Conformers

Cited by 53 publications

References 48 publications

Structural variants of yeast prions show conformer‐specific requirements for chaperone activity

Structural variants of yeast prions show conformer‐specific requirements for chaperone activity

Defining Hsp70 Subnetworks in Dengue Virus Replication Reveals Key Vulnerability in Flavivirus Infection

LGMDD1 natural history and phenotypic spectrum: Implications for clinical trials

Contact Info

Product

Resources

About