Raw data belongs to the publication: "Cohen et al. Haemoplasmas in wild rodents: routes of t... more Raw data belongs to the publication: "Cohen et al. Haemoplasmas in wild rodents: routes of transmission and infection dynamics" Molecular Ecology, 2018
An important hallmark of aging-and particularly of neurodegeneration-is the loss of proteostasis,... more An important hallmark of aging-and particularly of neurodegeneration-is the loss of proteostasis, which often leads to cellular stress responses and even cell death. However, the causal mechanisms driving proteostasis are unclear. Here, we show that SIRT6 has a critical role in maintaining proteostasis. It negatively regulates global translation by controlling ribosomal genes, nucleolar function and TIP5 chromatin localization. SIRT6 deletion dramatically increases nucleolar size, rRNA production and protein translation. However, the expression of protein-folding genes remains unchanged, failing to compensate for excessive translation, hence leading to reduced protein folding capacity and the production of aggregates. In vivo, we establish a C. elegans model (sir-2.4 KO) that shows reduced heat shock resistance and an accelerated age-dependent reduction in motility. Sir-2.4 depletion in a neuronspeci c protein aggregation-prone polyQ strain led to premature motility loss indicative of motor neuron dysfunction. These results point to proteostasis-stress intolerance in the absence of the SIRT6 ortholog that can be rescued by pharmacologically reducing protein translation rates. Together, our data suggest that SIRT6 de ciency in aging and neurodegeneration contributes to proteostasis loss through gene dysregulation of nucleolar function and the translation machinery. These results highlight that de cient proteostasis is the consequence of chromatin dysregulation that ultimately leads to neurodegeneration.
Proteins play a critical role in the cell, and the correct folding of a protein is often performe... more Proteins play a critical role in the cell, and the correct folding of a protein is often performed by a specialized group of proteinsmolecular chaperones-yet this is quite a delicate mission that can easily be disrupted. A protein might be mis-or unfolded by suboptimal temperature, redox state, ionic balance, or other negative factors. Furthermore, the gradual loss of protein homeostasis (proteostasis) is one of the hallmarks of several pathologies and of aging (López-Otín et al., 2013). Thus, many resources are invested in understanding this machinery and in finding possible treatments. A possible solution is the use of chemical chaperones which help fold proteins. One such suggested-and frequently mentionedmolecule is 4-phenylbutyric acid (4PBA). This molecule affects the
Detailed description of methods and results explaining why the two target bacterial lineages were... more Detailed description of methods and results explaining why the two target bacterial lineages were chosen.
Loss of proteostasis can occur due to mutations, the formation of aggregates, or general deficien... more Loss of proteostasis can occur due to mutations, the formation of aggregates, or general deficiency in the correct translation and folding of proteins. These phenomena are commonly observed in pathologies, but most significantly, loss of proteostasis characterizes aging. This loss leads to the chronic activation of stress responses and has a generally deleterious impact on the organism. While finding molecules that can alleviate these symptoms is an important step toward solutions for these conditions, some molecules might be mischaracterized on the way. 4‐phenylbutyric acid (4PBA) is known for its role as a chemical chaperone that helps alleviate endoplasmic reticulum (ER) stress, yet a scan of the literature reveals that no biochemical or molecular experiments have shown any protein refolding capacity. Here, we show that 4PBA is a conserved weak inhibitor of mRNA translation, both in vitro and in cellular systems, and furthermore—it does not promote protein folding nor prevents ag...
Highlights d DNA damage or SIRT6 absence leads to acetylation of Tau-K174 via CBP d Tau174ac shut... more Highlights d DNA damage or SIRT6 absence leads to acetylation of Tau-K174 via CBP d Tau174ac shuttles to the nucleus, where it induces nucleolar activation d SIRT6 regulates Tau-174ac nuclear functions through its deacetylation d Tau174Q increases nucleolar activity and protein synthesis, leading to ATP depletion
Journal of Molecular Microbiology and Biotechnology, 2011
Access to full text and tables of contents, including tentative ones for forthcoming issues: www.... more Access to full text and tables of contents, including tentative ones for forthcoming issues: www.karger.com/xxx_issues 96 Activity of the Two-Component Regulatory System CiaRH in 236 Recombinant Gluconacetobacter diazotrophicus Containing Cry1Ac Gene Codes for 130-kDa Toxin Protein
File List Statistical Analysis.R (MD5: 823be4f5fd071a36a1d2c79d0d3de0bd) Description The basic R ... more File List Statistical Analysis.R (MD5: 823be4f5fd071a36a1d2c79d0d3de0bd) Description The basic R code for the host-specificity and model selection analyses.
File List DataFor_glmmADMB.csv (MD5: 8945235dd0e6762d3230671eb51c540c) Description DataFor_glmmAD... more File List DataFor_glmmADMB.csv (MD5: 8945235dd0e6762d3230671eb51c540c) Description DataFor_glmmADMB.csv: Raw data for the host-specificity and model selection analyses Description of variables used for the host-specificity and model selection analyses: -- TABLE: Please see in attached file. --
Several parameters of phage T4 adsorption to and growth in Escherichia coli B/r were determined. ... more Several parameters of phage T4 adsorption to and growth in Escherichia coli B/r were determined. All changed monotonously with the bacterial growth rate (p), which was modified by nutritional conditions. Adsorption rate was faster at higher p values, positively correlated to cell size, and increased by pretreatment with low penicillin (Pn) concentrations; it was directly proportional to total cellular surface area, indicating a constant density of 14 receptors on cell envelopes irrespective of growth conditions. Parameters of phage development and cell lysis were pdependent. The rate of phage release and burst size increased, while the eclipse and latent periods decreased with increasing p. Differentiation between the contribution of several physiological parameters to the development of 14 was performed by manipulating the host cells. A competitive inhibitor of glucose uptake, methyl a-o-glucoside, was exploited to reduce the growth rate in the same effective carbon source. Synchro...
Planes of successive divisions in Escherichia coli have been proposed to be either parallel or pe... more Planes of successive divisions in Escherichia coli have been proposed to be either parallel or perpendicular to each other, restricted to one or two dimensions. To test the hypothesis that divisions can occur in planes alternating in three dimensions, a method was developed to generate cells with secondary constrictions during growth in suspension. The method involves a combination of thymine limitation (to manipulate chromosome replication rate) and mecillinam treatment (to inhibit penicillin-binding protein 2). The former modifies timing of terminations, the latter results in spheroidal cells. Such cells displayed secondary constrictions after adding deoxyguanosine (accelerating replication rate), thus temporarily enhancing division signals. The successive constrictions were seen to develop in planes that were tilted relative to each other, and in positions related to those of the nucleoids, visualized by staining with DAPI (4',6-diamidino-2-phenylindole dihydrochloride hydrat...
BACKGROUND: Conventional methods often fail to control the flatheaded borers Capnodis spp., major... more BACKGROUND: Conventional methods often fail to control the flatheaded borers Capnodis spp., major pests of stone fruit trees; the larvae are protected from insecticides and predation because they feed deep in the roots. A potential solution is transgenic trees producing in their roots toxic compounds such as Cry proteins of Bacillus thuringiensis (Bt). RESULTS: Toxicities against Capnodis larvae were demonstrated by exploiting a recently designed artificial larval diet and an available collection of field isolated Bt. An isolate of Bt tenebrionis (Btt) from commercial bioinsecticide (Novodor) displayed LC 50 and LC 95 values of 3.2 and 164 mg g −1 , respectively, against neonates of Capnodis tenebrionis, whereas values of the most toxic field isolate K-7 were 1.9 and 25.6 mg g −1 respectively. Weights of surviving larvae after 1 month on diets containing low concentrations of K-7 (0.1-1.0 mg g −1) were lower than on Btt or untreated larvae. K-7 was also toxic against larvae of C. cariosa and C. miliaris and found to harbour genes encoding Cry9Ea-like and Cry23Aa/Cry37Aa binary toxins. CONCLUSION: Larvae of Capnodis spp. are susceptible to Bt Cry toxins. Expressing cry genes active against these pests thus seems a feasible solution towards production of transgenic rootstock trees resilient to the pest.
Supplementary Table 2. GSEA clusters summarizing table. comparison name WT vs KO WT vs old Old vs... more Supplementary Table 2. GSEA clusters summarizing table. comparison name WT vs KO WT vs old Old vs KO KO vs WT old vs WT KO vs Old direction downregulated downregulated downregulated upregulated upregulated upregulated up/down in KO Old KO (comp. to Old) KO Old KO (comp. to Old)
Raw data belongs to the publication: "Cohen et al. Haemoplasmas in wild rodents: routes of t... more Raw data belongs to the publication: "Cohen et al. Haemoplasmas in wild rodents: routes of transmission and infection dynamics" Molecular Ecology, 2018
An important hallmark of aging-and particularly of neurodegeneration-is the loss of proteostasis,... more An important hallmark of aging-and particularly of neurodegeneration-is the loss of proteostasis, which often leads to cellular stress responses and even cell death. However, the causal mechanisms driving proteostasis are unclear. Here, we show that SIRT6 has a critical role in maintaining proteostasis. It negatively regulates global translation by controlling ribosomal genes, nucleolar function and TIP5 chromatin localization. SIRT6 deletion dramatically increases nucleolar size, rRNA production and protein translation. However, the expression of protein-folding genes remains unchanged, failing to compensate for excessive translation, hence leading to reduced protein folding capacity and the production of aggregates. In vivo, we establish a C. elegans model (sir-2.4 KO) that shows reduced heat shock resistance and an accelerated age-dependent reduction in motility. Sir-2.4 depletion in a neuronspeci c protein aggregation-prone polyQ strain led to premature motility loss indicative of motor neuron dysfunction. These results point to proteostasis-stress intolerance in the absence of the SIRT6 ortholog that can be rescued by pharmacologically reducing protein translation rates. Together, our data suggest that SIRT6 de ciency in aging and neurodegeneration contributes to proteostasis loss through gene dysregulation of nucleolar function and the translation machinery. These results highlight that de cient proteostasis is the consequence of chromatin dysregulation that ultimately leads to neurodegeneration.
Proteins play a critical role in the cell, and the correct folding of a protein is often performe... more Proteins play a critical role in the cell, and the correct folding of a protein is often performed by a specialized group of proteinsmolecular chaperones-yet this is quite a delicate mission that can easily be disrupted. A protein might be mis-or unfolded by suboptimal temperature, redox state, ionic balance, or other negative factors. Furthermore, the gradual loss of protein homeostasis (proteostasis) is one of the hallmarks of several pathologies and of aging (López-Otín et al., 2013). Thus, many resources are invested in understanding this machinery and in finding possible treatments. A possible solution is the use of chemical chaperones which help fold proteins. One such suggested-and frequently mentionedmolecule is 4-phenylbutyric acid (4PBA). This molecule affects the
Detailed description of methods and results explaining why the two target bacterial lineages were... more Detailed description of methods and results explaining why the two target bacterial lineages were chosen.
Loss of proteostasis can occur due to mutations, the formation of aggregates, or general deficien... more Loss of proteostasis can occur due to mutations, the formation of aggregates, or general deficiency in the correct translation and folding of proteins. These phenomena are commonly observed in pathologies, but most significantly, loss of proteostasis characterizes aging. This loss leads to the chronic activation of stress responses and has a generally deleterious impact on the organism. While finding molecules that can alleviate these symptoms is an important step toward solutions for these conditions, some molecules might be mischaracterized on the way. 4‐phenylbutyric acid (4PBA) is known for its role as a chemical chaperone that helps alleviate endoplasmic reticulum (ER) stress, yet a scan of the literature reveals that no biochemical or molecular experiments have shown any protein refolding capacity. Here, we show that 4PBA is a conserved weak inhibitor of mRNA translation, both in vitro and in cellular systems, and furthermore—it does not promote protein folding nor prevents ag...
Highlights d DNA damage or SIRT6 absence leads to acetylation of Tau-K174 via CBP d Tau174ac shut... more Highlights d DNA damage or SIRT6 absence leads to acetylation of Tau-K174 via CBP d Tau174ac shuttles to the nucleus, where it induces nucleolar activation d SIRT6 regulates Tau-174ac nuclear functions through its deacetylation d Tau174Q increases nucleolar activity and protein synthesis, leading to ATP depletion
Journal of Molecular Microbiology and Biotechnology, 2011
Access to full text and tables of contents, including tentative ones for forthcoming issues: www.... more Access to full text and tables of contents, including tentative ones for forthcoming issues: www.karger.com/xxx_issues 96 Activity of the Two-Component Regulatory System CiaRH in 236 Recombinant Gluconacetobacter diazotrophicus Containing Cry1Ac Gene Codes for 130-kDa Toxin Protein
File List Statistical Analysis.R (MD5: 823be4f5fd071a36a1d2c79d0d3de0bd) Description The basic R ... more File List Statistical Analysis.R (MD5: 823be4f5fd071a36a1d2c79d0d3de0bd) Description The basic R code for the host-specificity and model selection analyses.
File List DataFor_glmmADMB.csv (MD5: 8945235dd0e6762d3230671eb51c540c) Description DataFor_glmmAD... more File List DataFor_glmmADMB.csv (MD5: 8945235dd0e6762d3230671eb51c540c) Description DataFor_glmmADMB.csv: Raw data for the host-specificity and model selection analyses Description of variables used for the host-specificity and model selection analyses: -- TABLE: Please see in attached file. --
Several parameters of phage T4 adsorption to and growth in Escherichia coli B/r were determined. ... more Several parameters of phage T4 adsorption to and growth in Escherichia coli B/r were determined. All changed monotonously with the bacterial growth rate (p), which was modified by nutritional conditions. Adsorption rate was faster at higher p values, positively correlated to cell size, and increased by pretreatment with low penicillin (Pn) concentrations; it was directly proportional to total cellular surface area, indicating a constant density of 14 receptors on cell envelopes irrespective of growth conditions. Parameters of phage development and cell lysis were pdependent. The rate of phage release and burst size increased, while the eclipse and latent periods decreased with increasing p. Differentiation between the contribution of several physiological parameters to the development of 14 was performed by manipulating the host cells. A competitive inhibitor of glucose uptake, methyl a-o-glucoside, was exploited to reduce the growth rate in the same effective carbon source. Synchro...
Planes of successive divisions in Escherichia coli have been proposed to be either parallel or pe... more Planes of successive divisions in Escherichia coli have been proposed to be either parallel or perpendicular to each other, restricted to one or two dimensions. To test the hypothesis that divisions can occur in planes alternating in three dimensions, a method was developed to generate cells with secondary constrictions during growth in suspension. The method involves a combination of thymine limitation (to manipulate chromosome replication rate) and mecillinam treatment (to inhibit penicillin-binding protein 2). The former modifies timing of terminations, the latter results in spheroidal cells. Such cells displayed secondary constrictions after adding deoxyguanosine (accelerating replication rate), thus temporarily enhancing division signals. The successive constrictions were seen to develop in planes that were tilted relative to each other, and in positions related to those of the nucleoids, visualized by staining with DAPI (4',6-diamidino-2-phenylindole dihydrochloride hydrat...
BACKGROUND: Conventional methods often fail to control the flatheaded borers Capnodis spp., major... more BACKGROUND: Conventional methods often fail to control the flatheaded borers Capnodis spp., major pests of stone fruit trees; the larvae are protected from insecticides and predation because they feed deep in the roots. A potential solution is transgenic trees producing in their roots toxic compounds such as Cry proteins of Bacillus thuringiensis (Bt). RESULTS: Toxicities against Capnodis larvae were demonstrated by exploiting a recently designed artificial larval diet and an available collection of field isolated Bt. An isolate of Bt tenebrionis (Btt) from commercial bioinsecticide (Novodor) displayed LC 50 and LC 95 values of 3.2 and 164 mg g −1 , respectively, against neonates of Capnodis tenebrionis, whereas values of the most toxic field isolate K-7 were 1.9 and 25.6 mg g −1 respectively. Weights of surviving larvae after 1 month on diets containing low concentrations of K-7 (0.1-1.0 mg g −1) were lower than on Btt or untreated larvae. K-7 was also toxic against larvae of C. cariosa and C. miliaris and found to harbour genes encoding Cry9Ea-like and Cry23Aa/Cry37Aa binary toxins. CONCLUSION: Larvae of Capnodis spp. are susceptible to Bt Cry toxins. Expressing cry genes active against these pests thus seems a feasible solution towards production of transgenic rootstock trees resilient to the pest.
Supplementary Table 2. GSEA clusters summarizing table. comparison name WT vs KO WT vs old Old vs... more Supplementary Table 2. GSEA clusters summarizing table. comparison name WT vs KO WT vs old Old vs KO KO vs WT old vs WT KO vs Old direction downregulated downregulated downregulated upregulated upregulated upregulated up/down in KO Old KO (comp. to Old) KO Old KO (comp. to Old)
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