Netta Shemesh

Weed control is essential in modern agriculture, though it has become more difficult with the emergence of resistance to most current herbicides and a slow registration process of new compounds. A new approach to identify possible herbicide candidates using an artificial intelligence algorithm that takes into effect biological parameters with the g...

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...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Label-free, non-contact imaging with mechanical contrast and optical sectioning is a substantial challenge in microscopy. Spontaneous Brillouin scattering microscopy meets this challenge, but encounters a trade-off between acquisition speed and the specificity for biomechanical constituents with overlapping Brillouin bands. Stimulated Brillouin sca...

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....

Protein homeostasis is remodeled early in Caenorhabditis elegans adulthood, resulting in a sharp decline in folding capacity and reduced ability to cope with chronic and acute stress. Endocrine signals from the reproductive system can ameliorate this proteostatic collapse and reshape the quality control network. Given that environmental conditions,...

A longstanding puzzle in human genetics is what limits the clinical manifestation of hundreds of hereditary diseases to certain tissues, while their causal genes are expressed throughout the human body. A general conception is that tissue-selective disease phenotypes emerge when masking factors operate in unaffected tissues, but are specifically ab...

The causal genes, paralogs and respective disease-manifesting tissues. (DOCX)

The read counts and samples used in this study. (XLSX)

The distributions of causal genes (red bars) and paralogs (blue bars) by number of expressing tissues. (TIF)

Tissue-selective hereditary diseases and their disease-manifesting tissues. (DOCX)

The ratios between the expression levels of causal genes and their paralogs shown separately for causal genes sharing the same disease tissue. Each point represents the ratio observed in the disease tissue (red) and in an unaffected tissue (gray). The panels show genes causal for diseases manifesting in the liver (A), testis (B), thyroid (C). (TIF)

The ratio between the expression levels of causal genes and their paralogs visualized according to the differential expression of the causal gene and its paralog. Each point represents the ratio of a specific pair in their disease tissue (DT) and unaffected tissues (UAT). Colors indicate whether in the disease tissue the causal gene was significant...

The general difference in expression patterns between paralogs. Shown are the expression ratios for 2,257 unique paralog pairs (not filtered for causal genes) in the seven disease-related tissues. The median ratios between paralogs observed per tissue ranged between 1.03–1.08 (namely ~0 on a log scale), suggesting that the general difference in exp...

The median ratios between the expression levels of causal genes and their paralogs across tissues. Each row corresponds to genes causal for diseases that manifest in the tissue designated on the left, and represents the median ratios per tissue normalized to the maximum in that row. In each row, the median ratios in the disease tissue are highest....

A new mechanism for clearing protein damage from maturing oocytes has been described in a recent study by Bohnert and Kenyon (2017), who demonstrated that sperm-secreted hormones activate a vascular H+-ATPase pump that acidifies lysosomes and thus restores protein homeostasis.

A longstanding puzzle in human genetics is what limits the clinical manifestation of hundreds of hereditary diseases to certain tissues or cell types, while their causal genes are present and expressed throughout the human body. Here we considered a possible role for paralogs of causal genes in affecting this tissue selectivity. It has been shown a...

Cell-non-autonomous signals dictate the functional state of cellular quality control systems, remodeling the ability of cells to cope with stress and maintain protein homeostasis (proteostasis). One highly regulated cell-non-autonomous switch controls proteostatic capacity in Caenorhabditis elegans adulthood. Signals from the reproductive system do...

Caenorhabditis elegans somatic protein homeostasis (proteostasis) is actively remodeled at the onset of reproduction. This proteostatic collapse is regulated cell-nonautonomously by signals from the reproductive system that transmit the commitment to reproduction to somatic cells. Here, we asked whether the link between the reproductive system and...

Protein phosphorylation underlies cellular response pathways across eukaryotes and is governed by the opposing actions of phosphorylating kinases and de-phosphorylating phosphatases. While kinases and phosphatases have been extensively studied, their organization and the mechanisms by which they balance each other are not well understood. To addres...

The transcriptional responses and protein half-lives of kinases and phosphatases in budding yeast. A The percentage of genes that are differentially expressed in at least one of the experiments reported by Kemmeren et al. [17]. The fraction of differentially expressed kinases and phosphatases is significantly lower relative to all genes (p = 0.001...

Differences in gene numbers, protein abundance, essentiality and protein-protein interactions between curated kinases and phosphatases. We repeated our analyses using lists of curated kinases and phosphatases from the following organism-specific databases: Saccharomyces Genome Database (SGD) for yeast, The Arabidopsis Information Resource (TAIR) fo...

The percentages of kinases and phosphatases that were characterized in the phospho-proteomic analysis of Bodenmiller et al.[9]. 'Detected' enzymes denote phosphorylation enzymes that contain a peptide whose abundance was measured. 'Inactivated' enzymes denote phosphorylation enzymes for which a strain carrying the inactivated enzyme was profiled. T...

Primer sequences used to measure mRNA levels for the validation of RNAi knock-down in C. elegans. (XLSX)

Differences in gene numbers, protein abundance and essentiality between tyrosine-kinases and tyrosine-phosphatases. The list of tyrosine kinases and phosphatases was created by gathering from Gene Ontology (GO) proteins annotated to 'protein tyrosine kinase activity' (GO:0004713) and to 'protein tyrosine phosphatase activity' (GO:0004725). From the...

The distinct impact of kinase layers when limiting each layer to kinases that were fully measured. Each layer contained only kinases that were both inactivated and detected in Bodenmiller et al. [9], including 14 top-layer kinases (TOP#), 26 middle-layer kinases (MID#), and 11 bottom-layer kinases (BOT#). Note that the middle layer was unchanged (M...

A listing of yeast kinases and phosphatases and the association of kinases to layers in the impact hierarchy. (XLSX)

Validations for the impact hierarchy of budding yeast kinases. A The impact of kinases from each layer on the phospho-proteome. The numbers of proteins with altered phosphorylation upon kinase inactivation, for kinases from each layer, decreased upon moving down the kinase hierarchy. Inactivation of top-layer kinases affected the phosphorylation o...

The distinct impact of kinase layers upon reconstructing the hierarchy using more stringent thresholds. The revised hierarchy consisted of 216 kinase-kinase relationships involving 29 top-layer kinases (TOP*), 16 middle-layer kinases (MID*) and 24 bottom-layer kinases (BOT*). A The impact of kinases on phosphorylation of proteins, as measured by t...

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)

Quality control is an essential aspect of cellular function, with protein folding quality control being carried out by molecular chaperones, a diverse group of highly conserved proteins that specifically identify misfolded conformations. Molecular chaperones are thus required to support proteins affected by expressed polymorphisms, mutations, intri...

Protein folding and clearance machineries are required for the maintenance and function of the proteome. Quality control systems and activation of stress signaling pathways have, therefore, profound consequences on the long-term health of the cell and, by extension, on lifespan. Aging is associated with loss of cellular function, increased vulnerab...

Protein folding and clearance networks sense and respond to misfolded and aggregation-prone proteins by activating cytoprotective cell stress responses that safeguard the proteome against damage, maintain the health of the cell, and enhance lifespan. Surprisingly, cellular proteostasis undergoes a sudden and widespread failure early in Caenorhabdit...

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...

All cells rely on highly conserved protein folding and clearance pathways to detect and resolve protein damage and to maintain protein homeostasis (proteostasis). Because age is associated with an imbalance in proteostasis, there is a need to understand how protein folding is regulated in a multi-cellular organism that undergoes aging. We have obse...