Shiran Dror

Heidelberg University · Center for Molecular Biology (ZMBH)

The sensitivity of the protein-folding environment to chaperone disruption can be highly tissue-specific. Yet, the organization of the chaperone system across physiological human tissues has received little attention. Through computational analyses of large-scale tissue transcriptomes, we unveil that the chaperone system is composed of core element...

Correct folding and assembly of proteins and protein complexes are essential for cellular function. Cells employ quality control pathways that correct, sequester or eliminate damaged proteins to maintain a healthy proteome, thus ensuring cellular proteostasis and preventing further protein damage. Because of redundant functions within the proteosta...

The sensitivity of the protein-folding environment to chaperone disruption can be highly tissue-specific. Yet, the organization of the chaperone system across physiological human tissues has received little attention. Here, we used human tissue RNA-sequencing profiles to analyze the expression and organization of chaperones across 29 main tissues....

Safeguarding the proteome is central to the health of the cell. In multi-cellular organisms, the composition of the proteome, and by extension, protein-folding requirements, varies between cells. In agreement, chaperone network composition differs between tissues. Here, we ask how chaperone expression is regulated in a cell type-specific manner and...

Transcriptional analysis of muscle gene expression. Hierarchical clustering of the relative expression of 35 muscle-specific genes across 10 developmental stages (at 4-cells, E cell division, 4th-7th AB cell divisions, ventral enclosure (VE), comma stage (cs), first movement, and L1) [55]. MI marks the myogenesis-induced subset. (TIF)

Modulating HSP90 levels results in embryo arrest. (A) Images of a population of wild type, unc-54(ts), HSP90M or HSP90M;unc-54(ts) embryos laid at 20°C. (B) Representative confocal images (>90%) of unc-54(ts), and HSP90M;unc-54(ts) embryos laid at 25°C and stained with anti-UNC-54 antibodies. The scale bar is 25 μm. (TIF)

A mutation in the putative HLH-1-binding motif of daf-21(Hsp90) promoter affected its expression pattern in adult animals. Representative images of HLH-1(ec) animals expressing GFP under the regulation of the wild type or a mutant daf-21(Hsp90) promoter, without myogenic induction. Arrows indicate body-wall muscle cells. (TIF)

Chaperone association with muscle and HLH-1 binding. (A) Flowchart outlining the filtering analyses of the chaperone list. (B) Summarized data from bioinformatics analyses. (XLSX)

Heat shock-induced changes in chaperone expression. (A) Representative images (>90%) of the expression pattern of chaperones in wild type embryos untreated or subjected to heat shock after a 6 h recovery. Scale bar is 25 μm. (B-E) Relative chaperone mRNA levels in heat shock-treated wild type (gray) or HLH-1(ec) (red) embryos. Data are relative to...

Reduced HLH-1 levels modulate the expression of some chaperones. (A) Representative images (>90%) of the expression pattern of the indicated chaperones in wild type embryos grown at 25°C. (B-C) Relative mRNA levels (25/15°C) of wild type (gray) or hlh-1(cc561) (green) embryos (normalize to T07A9.15). Data are presented as means ± SEM of 5 independe...

Disruption of muscle proteostasis results in embryo arrest. (A) Embryonic arrest scored for Q35;hlh-1(cc561) or Q35 embryos treated with smg-2, smg-7 or empty vector control RNAi. Data are presented as means ± SEM of at least 3 independent experiments. (B) Representative confocal images of Q35;hlh-1(cc561) muscles. Scale bar is 10 μm. (C-D) Extract...

Down-regulation of hsp-1(Hsc70), rme-8(Hsp40) and dnj-8(Hsp40) in DNJ-24M animals disrupts myosin organization. Representative confocal images of age-synchronized DNJ-24M animals treated with control, hsp-1(Hsc70), rme-8(Hsp40) or dnj-8(Hsp40) RNAi and stained with anti-MYO-3 antibodies. Scale bar is 25 μm. (TIF)

List of strains used in this study. (PDF)

List of quantitative PCR primers used in this study. (PDF)

Proteome stability is central to cellular function and the lifespan of an organism. This is apparent in muscle cells, where incorrect folding and assembly of the sarcomere contributes to disease and aging. Apart from the myosin-assembly factor UNC-45, the complete network of chaperones involved in assembly and maintenance of muscle tissue is curren...

The folding and assembly of proteins is essential for protein function, the long-term health of the cell, and longevity of the organism. Historically, the function and regulation of protein folding was studied in vitro, in isolated tissue culture cells and in unicellular organisms. Recent studies have uncovered links between protein homeostasis (pr...