Graded Proteasome Dysfunction in Caenorhabditis elegans Activates an Adaptive Response Involving the Conserved SKN-1 and ELT-2 Transcription Factors and the Autophagy-Lysosome Pathway
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{"title"=>"Graded Proteasome Dysfunction in Caenorhabditis elegans Activates an Adaptive Response Involving the Conserved SKN-1 and ELT-2 Transcription Factors and the Autophagy-Lysosome Pathway", "type"=>"journal", "authors"=>[{"first_name"=>"Scott A.", "last_name"=>"Keith", "scopus_author_id"=>"56113370700"}, {"first_name"=>"Sarah K.", "last_name"=>"Maddux", "scopus_author_id"=>"56884522800"}, {"first_name"=>"Yayu", "last_name"=>"Zhong", "scopus_author_id"=>"57155633500"}, {"first_name"=>"Meghna N.", "last_name"=>"Chinchankar", "scopus_author_id"=>"57156435300"}, {"first_name"=>"Annabel A.", "last_name"=>"Ferguson", "scopus_author_id"=>"35076006700"}, {"first_name"=>"Arjumand", "last_name"=>"Ghazi", "scopus_author_id"=>"57196840085"}, {"first_name"=>"Alfred L.", "last_name"=>"Fisher", "scopus_author_id"=>"8756230700"}], "year"=>2016, "source"=>"PLoS Genetics", "identifiers"=>{"scopus"=>"2-s2.0-84959863448", "sgr"=>"84959863448", "issn"=>"15537404", "doi"=>"10.1371/journal.pgen.1005823", "pmid"=>"26828939", "isbn"=>"1553-7404 (Electronic)\r1553-7390 (Linking)", "pui"=>"608905438"}, "id"=>"d79439d1-c11b-37e9-813d-5de425226af4", "abstract"=>"The maintenance of cellular proteins in a biologically active and structurally stable state is a vital endeavor involving multiple cellular pathways. One such pathway is the ubiquitin-proteasome system that represents a major route for protein degradation, and reductions in this pathway usually have adverse effects on the health of cells and tissues. Here, we demonstrate that loss-of-function mutants of the Caenorhabditis elegans proteasome subunit, RPN-10, exhibit moderate proteasome dysfunction and unexpectedly develop both increased longevity and enhanced resistance to multiple threats to the proteome, including heat, oxidative stress, and the presence of aggregation prone proteins. The rpn-10 mutant animals survive through the activation of compensatory mechanisms regulated by the conserved SKN-1/Nrf2 and ELT-2/GATA transcription factors that mediate the increased expression of genes encoding proteasome subunits as well as those mediating oxidative- and heat-stress responses. Additionally, we find that the rpn-10 mutant also shows enhanced activity of the autophagy-lysosome pathway as evidenced by increased expression of the multiple autophagy genes including atg-16.2, lgg-1, and bec-1, and also by an increase in GFP::LGG-1 puncta. Consistent with a critical role for this pathway, the enhanced resistance of the rpn-10 mutant to aggregation prone proteins depends on autophagy genes atg-13, atg-16.2, and prmt-1. Furthermore, the rpn-10 mutant is particularly sensitive to the inhibition of lysosome activity via either RNAi or chemical means. We also find that the rpn-10 mutant shows a reduction in the numbers of intestinal lysosomes, and that the elt-2 gene also plays a novel and vital role in controlling the production of functional lysosomes by the intestine. Overall, these experiments suggest that moderate proteasome dysfunction could be leveraged to improve protein homeostasis and organismal health and longevity, and that the rpn-10 mutant provides a unique platform to explore these possibilities. ", "link"=>"http://www.mendeley.com/research/graded-proteasome-dysfunction-caenorhabditis-elegans-activates-adaptive-response-involving-conserved", "reader_count"=>36, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>3, "Researcher"=>9, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>12, "Student > Postgraduate"=>1, "Student > Master"=>3, "Other"=>2, "Student > Bachelor"=>4}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>3, "Researcher"=>9, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>12, "Student > Postgraduate"=>1, "Student > Master"=>3, "Other"=>2, "Student > Bachelor"=>4}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>7, "Agricultural and Biological Sciences"=>23, "Medicine and Dentistry"=>3, "Neuroscience"=>2}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>3}, "Neuroscience"=>{"Neuroscience"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>23}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>7}, "Unspecified"=>{"Unspecified"=>1}}, "reader_count_by_country"=>{"United States"=>1, "United Kingdom"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/4266862"], "description"=>"<p>Compared to wild-type N2 worms, the adult <i>rpn-10(ok1865)</i> mutant shows enhanced resistance to external and internal stresses, including (A) survival during a 35°C heat shock (n = 81 for <i>rpn-10</i> and = 80 for N2, p < 0.0001 by log-rank test), (B) survival following exposure to 7 mM <i>tert</i>-butyl hydroperoxide (tBHP) (n = 107 for <i>rpn-10</i> and = 95 for N2, p < 0.0001 by log-rank test), and the number of aggregates formed when a Q35::YFP fusion protein is expressed in the muscle (C and D) (n = 60 for WT and <i>rpn-10</i>, p<0.0001 by <i>t-</i>test). The Q35::YFP aggregates seen in the <i>rpn-10</i> mutant are also smaller than those seen in the wild-type animals (E). The <i>rpn-10</i> mutant also shows a reduction in the percentage of animals showing protein aggregates when a Q44::YFP fusion protein is expressed in the intestine using an integrated transgene (F and G) (n = 100 for WT and <i>rpn-10</i>, p < 0.003 by <i>t</i>-test). Moreover, the <i>unc-54(e1157)</i> mutant is protected from developing paralysis produced by a shift from 16°C (permissive temperature) to 25°C (restrictive temperature) by the <i>rpn-10</i> mutation (H) (n = 317 for <i>unc-54(e1157)</i> and n = 284 for <i>rpn-10</i>, <i>unc-54</i>, p < 0.0001 by Fisher’s exact test).</p>", "links"=>[], "tags"=>["lysosome", "SKN", "proteasome dysfunction", "Caenorhabditis elegans proteasome subunit", "atg", "Graded Proteasome Dysfunction", "ELT", "rpn", "protein", "pathway", "RPN", "Caenorhabditis elegans Activates", "GFP", "genes encoding proteasome subunits"], "article_id"=>2616706, "categories"=>["Biophysics", "Biochemistry", "Microbiology", "Cell Biology", "Genetics", "Molecular Biology", "Neuroscience", "Immunology", "Biological Sciences not elsewhere classified", "Developmental Biology", "Infectious Diseases", "Plant Biology", "Computational Biology"], "users"=>["Scott A. Keith", "Sarah K. Maddux", "Yayu Zhong", "Meghna N. Chinchankar", "Annabel A. Ferguson", "Arjumand Ghazi", "Alfred L. Fisher"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005823.g002", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/The_i_rpn_10_i_mutant_shows_enhanced_resistance_to_proteostasis_threats_/2616706", "title"=>"The <i>rpn-10</i> mutant shows enhanced resistance to proteostasis threats.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2016-02-01 00:11:10"}
  • {"files"=>["https://ndownloader.figshare.com/files/4267129"], "description"=>"<p>Control of lysosome gene expression by <i>elt-2</i>.</p>", "links"=>[], "tags"=>["lysosome", "SKN", "proteasome dysfunction", "Caenorhabditis elegans proteasome subunit", "atg", "Graded Proteasome Dysfunction", "ELT", "rpn", "protein", "pathway", "RPN", "Caenorhabditis elegans Activates", "GFP", "genes encoding proteasome subunits"], "article_id"=>2616901, "categories"=>["Biophysics", "Biochemistry", "Microbiology", "Cell Biology", "Genetics", "Molecular Biology", "Neuroscience", "Immunology", "Biological Sciences not elsewhere classified", "Developmental Biology", "Infectious Diseases", "Plant Biology", "Computational Biology"], "users"=>["Scott A. Keith", "Sarah K. Maddux", "Yayu Zhong", "Meghna N. Chinchankar", "Annabel A. Ferguson", "Arjumand Ghazi", "Alfred L. Fisher"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005823.t001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Control_of_lysosome_gene_expression_by_i_elt_2_i_/2616901", "title"=>"Control of lysosome gene expression by <i>elt-2</i>.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2016-02-01 00:11:10"}
  • {"files"=>["https://ndownloader.figshare.com/files/4266832"], "description"=>"<p>(A) The expression of an RPN-10::GFP fusion protein from a fosmid-based transgene shows broad expression in the cytoplasm and nuclei (arrow) of multiple tissues including the intestine, pharynx, hypodermis, and germline. The GFP signal is produced from the <i>rpn-10</i> gene because it can be effectively silenced via treatment of the worms with <i>rpn-10</i> RNAi (B). (C) Quantification of GFP expression in digital images captured as in Panel B via the use of ImageJ. *** represents p = 0.001 by <i>t</i>-test. (D) Structure of the full-length RPN-10 protein showing the location of the N-terminal Von Willebrand factor A domain (VWA), the location of the highly conserved Asp-Asn-Ser-Glu (DNSE) sequence that is essential for the binding of RPN-10 to the 19S proteasome subunit, and the two C-terminal ubiquitin interacting domains (UID). The dotted line indicates the coding sequence regions deleted in the <i>rpn-10(ok1865)</i> allele, and this line extends beyond the N-terminus of the RPN-10 protein to highlight the extension of the deletion into the 5’ UTR of the <i>rpn-10</i> gene. (E) The <i>rpn-10(ok1865)</i> mutation disrupts UPS function as shown by the selective accumulation of a UbV::GFP fusion protein in the intestine of the mutant but not wild-type animals. In contrast, the <i>rpn-10</i> mutation has no effect on the expression of mCherry driven by the same promoter from a separate transgene in the animals. (F) Quantification of GFP expression from digital images captured as in Panel E. *** represents p<0.001 by <i>t-</i>test. (G) The accumulated UbV::GFP fusion protein is localized in the intestine except for the three proximal cells (arrow). (H) In addition to accumulating the UbV::GFP fusion protein, the <i>rpn-10</i> mutant induces the expression of the <i>aip-1p</i>::<i>GFP</i> reporter gene in multiple tissues along with the intestine. (I) Quantification of GFP expression from digital images captured as in Panel H. *** represents p<0.001 by <i>t</i>-test.</p>", "links"=>[], "tags"=>["lysosome", "SKN", "proteasome dysfunction", "Caenorhabditis elegans proteasome subunit", "atg", "Graded Proteasome Dysfunction", "ELT", "rpn", "protein", "pathway", "RPN", "Caenorhabditis elegans Activates", "GFP", "genes encoding proteasome subunits"], "article_id"=>2616679, "categories"=>["Biophysics", "Biochemistry", "Microbiology", "Cell Biology", "Genetics", "Molecular Biology", "Neuroscience", "Immunology", "Biological Sciences not elsewhere classified", "Developmental Biology", "Infectious Diseases", "Plant Biology", "Computational Biology"], "users"=>["Scott A. Keith", "Sarah K. Maddux", "Yayu Zhong", "Meghna N. Chinchankar", "Annabel A. Ferguson", "Arjumand Ghazi", "Alfred L. Fisher"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005823.g001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/RPN_10_is_broadly_expressed_and_contributes_to_UPS_activity_/2616679", "title"=>"RPN-10 is broadly expressed and contributes to UPS activity.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2016-02-01 00:11:10"}
  • {"files"=>["https://ndownloader.figshare.com/files/4267102"], "description"=>"<p>(A) Representative images of day 1 adult animals treated with control or <i>elt-2</i> RNAi and stained with the Magic Red dye specific for cathepsin B. (B) Images of animals captured as in panel A, but cropped instead of reduced in scale, to demonstrate details of the intestine. (C) Graph quantifying the effects of control and <i>elt-2</i> RNAi on Magic Red fluorescence (n = 15 for each RNAi treatment, p < 0.001 by <i>t-</i>test).</p>", "links"=>[], "tags"=>["lysosome", "SKN", "proteasome dysfunction", "Caenorhabditis elegans proteasome subunit", "atg", "Graded Proteasome Dysfunction", "ELT", "rpn", "protein", "pathway", "RPN", "Caenorhabditis elegans Activates", "GFP", "genes encoding proteasome subunits"], "article_id"=>2616871, "categories"=>["Biophysics", "Biochemistry", "Microbiology", "Cell Biology", "Genetics", "Molecular Biology", "Neuroscience", "Immunology", "Biological Sciences not elsewhere classified", "Developmental Biology", "Infectious Diseases", "Plant Biology", "Computational Biology"], "users"=>["Scott A. Keith", "Sarah K. Maddux", "Yayu Zhong", "Meghna N. Chinchankar", "Annabel A. Ferguson", "Arjumand Ghazi", "Alfred L. Fisher"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005823.g008", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_i_elt_2_i_controls_lysosome_formation_in_the_intestine_/2616871", "title"=>"<i>elt-2</i> controls lysosome formation in the intestine.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2016-02-01 00:11:10"}
  • {"files"=>["https://ndownloader.figshare.com/files/4267042"], "description"=>"<p>(A) Treatment of the <i>rpn-10</i> mutant, but not wild-type animals with <i>elt-2</i> RNAi results in a developmental arrest phenotype. (B) The <i>rpn-10</i> mutant shows elevated expression of GFP::LGG-1 as shown by fluorescence microscopy or measurement of the fluorescence in the images (C) (n = 10 for each genotype, p<0.001 by <i>t</i>-test). (D) The <i>rpn-10</i> mutant also shows an increase in GFP::LGG-1 puncta formation in both the intestine and in the seam cells as shown by fluorescence microscopy. Puncta are indicated by arrows. (E) Scoring of puncta number in the seam cells shows a significant increase in puncta count in the <i>rpn-10</i> mutant (n = 41 for WT and = 24 for <i>rpn-10</i>, *** represents p<0.0001 by <i>t-</i>test). (F) Measurement of puncta number in the intestine also demonstrates a significant increase in puncta number in the <i>rpn-10</i> mutant (n = 14 for WT and = 13 for <i>rpn-10</i>, *** represents p = 0.0024 by <i>t</i>-test). (G) The inhibition of autophagy with <i>an atg-13</i> mutation delays the developmental time of an <i>rpn-10; atg-13</i> mutant compared to the <i>rpn-10</i> or <i>atg-13</i> mutants and only 80% of worms reach adulthood (n = 283 for WT, = 298 for <i>rpn-10</i>, = 282 for <i>atg-13</i>, and = 300 for <i>rpn-10; atg-13</i>, p<0.0001 for differences between <i>atg-13; rpn-10</i> and <i>rpn-10</i> at the 88 hour time point by Fisher’s exact test) (H) The inhibition of autophagy in <i>rpn-10</i> mutant worms expressing a Q44::YFP transgene in the intestine through treatment with <i>atg-13</i>, <i>atg-16</i>.<i>2</i>, or <i>prmt-1</i> RNAi treatment, starting on day 1 of adulthood, reduces the protective effect of the <i>rpn-10</i> mutation. Shown are the percentage of animals with aggregates when scored after 72 hours of RNAi treatment (for <i>atg-13</i> RNAi, n = 50, p = 0.0002 by Fisher’s exact test; for <i>atg-16</i>.<i>2</i> RNAi, n = 50, p = 0.003; and <i>prmt-1</i> RNAi, n = 50, NS).</p>", "links"=>[], "tags"=>["lysosome", "SKN", "proteasome dysfunction", "Caenorhabditis elegans proteasome subunit", "atg", "Graded Proteasome Dysfunction", "ELT", "rpn", "protein", "pathway", "RPN", "Caenorhabditis elegans Activates", "GFP", "genes encoding proteasome subunits"], "article_id"=>2616814, "categories"=>["Biophysics", "Biochemistry", "Microbiology", "Cell Biology", "Genetics", "Molecular Biology", "Neuroscience", "Immunology", "Biological Sciences not elsewhere classified", "Developmental Biology", "Infectious Diseases", "Plant Biology", "Computational Biology"], "users"=>["Scott A. Keith", "Sarah K. Maddux", "Yayu Zhong", "Meghna N. Chinchankar", "Annabel A. Ferguson", "Arjumand Ghazi", "Alfred L. Fisher"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005823.g006", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_i_elt_2_i_is_required_for_the_viability_of_the_i_rpn_10_i_mutant_/2616814", "title"=>"<i>elt-2</i> is required for the viability of the <i>rpn-10</i> mutant.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2016-02-01 00:11:10"}
  • {"files"=>["https://ndownloader.figshare.com/files/4267081"], "description"=>"<p>(A) Representative images of day 1 adult wild-type and <i>rpn-10</i> mutant animals stained either with Lysotracker red, which accumulates in lysosomes due to the low pH environment of the organelle, or with Magic Red substrates that produce red fluorescence following proteolytic cleavage by cathepsin L or cathepsin B, respectively. (B) Quantification of the red fluorescence in images captured as in panel A (n > 9 for all genotypes, p = 0.0001 for WT vs <i>rpn-10</i> for Lysotracker red, = 0.0005 for Magic Red B, and = 0.0007 for Magic Red L). (C and D) High-magnification images of Lysotracker red stained animals, wild-type in C and <i>rpn-10</i> in D, captured as in panel A to demonstrate details of the intestine. GFP fluorescence indicates the intestinal nuclei as marked by an <i>elt-2p</i>::<i>GFP</i> reporter gene. (E and F) Images of animals stained with the Magic Red dye specific for cathepsin L, which are cropped similarly to panels C and D; GFP fluorescence indicates the intestinal nuclei. (G) Images showing the effects of treating wild-type and <i>rpn-10</i> mutant animals with <i>vha-15</i> RNAi. (H) Graph quantifying the effects of <i>vha-15</i> RNAi treatment on wild-type and <i>rpn-10</i> mutant animals (*** represents p = 0.0062 by <i>t-</i>test). (I) Images showing the developmental delay produced by treating the <i>rpn-10</i> mutant with 100 mM NH<sub>4</sub>Cl to neutralize lysosomal pH. (J) Graph showing the developmental effects of increasing NH<sub>4</sub>Cl doses on wild-type and <i>rpn-10</i> mutant animals.</p>", "links"=>[], "tags"=>["lysosome", "SKN", "proteasome dysfunction", "Caenorhabditis elegans proteasome subunit", "atg", "Graded Proteasome Dysfunction", "ELT", "rpn", "protein", "pathway", "RPN", "Caenorhabditis elegans Activates", "GFP", "genes encoding proteasome subunits"], "article_id"=>2616853, "categories"=>["Biophysics", "Biochemistry", "Microbiology", "Cell Biology", "Genetics", "Molecular Biology", "Neuroscience", "Immunology", "Biological Sciences not elsewhere classified", "Developmental Biology", "Infectious Diseases", "Plant Biology", "Computational Biology"], "users"=>["Scott A. Keith", "Sarah K. Maddux", "Yayu Zhong", "Meghna N. Chinchankar", "Annabel A. Ferguson", "Arjumand Ghazi", "Alfred L. Fisher"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005823.g007", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Lysosome_function_is_required_for_the_viability_of_the_i_rpn_10_i_mutant_/2616853", "title"=>"Lysosome function is required for the viability of the <i>rpn-10</i> mutant.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2016-02-01 00:11:10"}
  • {"files"=>["https://ndownloader.figshare.com/files/4267114"], "description"=>"<p>(A) The <i>ldIs7</i> and <i>caIs20</i> transgenes express either <i>skn-1</i> or <i>elt-2</i> as a GFP fusion protein under the control of the native promoter. Each transgene was crossed into the <i>rpn-10</i> mutant, which also has the endogenous <i>skn-1</i> or <i>elt-2</i> genes intact. Development of synchronized <i>rpn-10</i> and transgenic worms was measured and plotted as shown. (B) <i>rpn-10</i> mutant worms treated with <i>skn-1</i> or <i>hsf-1</i> RNAi starting at day 1 of adulthood did not show an increase in Q44::YFP aggregation in the intestine (n = 50 for WT and <i>rpn-10</i>). (C) Treatment with <i>skn-1</i> RNAi mitigates the extended lifespan phenotype seen in the <i>rpn-10</i> mutant when kept at 25°C from day 1 of adulthood. Mean lifespan for N2 on control RNAi is 13.0 days (n = 102) and 13.3 days on <i>skn-1</i> RNAi (n = 119). Mean lifespan for <i>rpn-10</i> on control RNAi is 16.7 days (n = 116) and is 13.8 days on <i>skn-1</i> RNAi (n = 126). Comparison of <i>rpn-10</i> mutant treated with control vs <i>skn-1</i> RNAi, p<0.0001 by log-rank test; comparison of N2 and <i>rpn-10</i> on control RNAi, p<0.0001 by log-rank test. (D) Treatment with <i>elt-2</i> RNAi has no effect on the extended lifespan of the <i>rpn-10</i> mutant at 25°C. Mean lifespan for N2 on control RNAi is 11.1 (n = 120) and is 10.4 days on <i>elt-2</i> RNAi (n = 113). Mean lifespan for <i>rpn-10</i> on control RNAi is 13.7 days (n = 113) and is 13.3 days on <i>elt-2</i> RNAi (n = 119). Comparison of <i>rpn-10</i> mutant treated with control vs <i>elt-2</i> RNAi, p<0.03 by log-rank test; comparison of N2 and <i>rpn-10</i> on control RNAi, p<0.0001 by log-rank test. (E) Model summarizing the effects of <i>skn-1</i> and <i>elt-2</i> in the <i>rpn-10</i> mutant and possibly other situations where proteasome function is reduced.</p>", "links"=>[], "tags"=>["lysosome", "SKN", "proteasome dysfunction", "Caenorhabditis elegans proteasome subunit", "atg", "Graded Proteasome Dysfunction", "ELT", "rpn", "protein", "pathway", "RPN", "Caenorhabditis elegans Activates", "GFP", "genes encoding proteasome subunits"], "article_id"=>2616886, "categories"=>["Biophysics", "Biochemistry", "Microbiology", "Cell Biology", "Genetics", "Molecular Biology", "Neuroscience", "Immunology", "Biological Sciences not elsewhere classified", "Developmental Biology", "Infectious Diseases", "Plant Biology", "Computational Biology"], "users"=>["Scott A. Keith", "Sarah K. Maddux", "Yayu Zhong", "Meghna N. Chinchankar", "Annabel A. Ferguson", "Arjumand Ghazi", "Alfred L. Fisher"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005823.g009", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Roles_of_i_skn_1_i_and_i_elt_2_i_in_the_development_lifespan_and_enhanced_proteostasis_of_the_i_rpn_10_i_mutant_/2616886", "title"=>"Roles of <i>skn-1</i> and <i>elt-2</i> in the development, lifespan, and enhanced proteostasis of the <i>rpn-10</i> mutant.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2016-02-01 00:11:10"}
  • {"files"=>["https://ndownloader.figshare.com/files/4266967"], "description"=>"<p>(A) The <i>rpn-10</i> mutant has an extended lifespan compared to wild-type animal in lifespan studies conducted at 25°C (mean lifespan 15.0 days for WT (n = 121) and 19.4 days for <i>rpn-10</i> (n = 120), p<0.0001 by log-rank test). (B) Shot-gun whole transcriptome sequencing (RNA-seq) was used to characterize and measure the transcriptome of N2 and <i>rpn-10(ok1865)</i> mutants. From these experiments, a total of 19,638 mRNA and other RNA transcripts were detected. To test for evidence of a proteasome subunit gene expression signature in the <i>rpn-10</i> mutant, Gene Set Association Analysis (GSAA) was used. GSAA calculates a differential expression score for each gene in the entire 19,638 gene RNA-seq dataset, and then uses a running weighted Kolmogorov-Smirnov test to examine association of an entire gene set with each phenotypic class. The strength of the association is measured by the association score (AS) where positive scores indicate association of the gene set with the phenotype, and statistical significance is measured by a false discovery rate (FDR) that is adjusted for multiple testing. From 32 proteasome subunit genes, 26 showed association with the <i>rpn-10</i> profile. AS represents the association score with positive values indicating association, and FDR represents the false discovery rate for the association. (C) GSAA provides evidence of an oxidative stress response gene signature in the <i>rpn-10</i> mutant. From the 895 genes up-regulated in worms exposed to oxidative stress [<a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005823#pgen.1005823.ref060\" target=\"_blank\">60</a>], 481 genes show association with the <i>rpn-10</i> profile, and among the 369 down-regulated genes, 136 show an association.</p>", "links"=>[], "tags"=>["lysosome", "SKN", "proteasome dysfunction", "Caenorhabditis elegans proteasome subunit", "atg", "Graded Proteasome Dysfunction", "ELT", "rpn", "protein", "pathway", "RPN", "Caenorhabditis elegans Activates", "GFP", "genes encoding proteasome subunits"], "article_id"=>2616760, "categories"=>["Biophysics", "Biochemistry", "Microbiology", "Cell Biology", "Genetics", "Molecular Biology", "Neuroscience", "Immunology", "Biological Sciences not elsewhere classified", "Developmental Biology", "Infectious Diseases", "Plant Biology", "Computational Biology"], "users"=>["Scott A. Keith", "Sarah K. Maddux", "Yayu Zhong", "Meghna N. Chinchankar", "Annabel A. Ferguson", "Arjumand Ghazi", "Alfred L. Fisher"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005823.g004", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/The_i_rpn_10_i_mutant_shows_increased_longevity_and_increased_expression_of_proteasome_and_oxidative_stress_response_genes_compared_to_wild_type_animals_/2616760", "title"=>"The <i>rpn-10</i> mutant shows increased longevity and increased expression of proteasome and oxidative stress response genes compared to wild-type animals.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2016-02-01 00:11:10"}
  • {"files"=>["https://ndownloader.figshare.com/files/4267006"], "description"=>"<p>(A) The <i>rpn-10</i> mutant shows activation of an <i>rpn-7p</i>::<i>GFP</i> reporter in multiple tissues including the pharynx, intestine, and hypodermis that is confirmed by quantifying the GFP fluorescence in the images (B) (n = 11 for WT and <i>rpn-10</i>, p <0.001 by <i>t-</i>test.) (C) Treating the <i>rpn-10</i> mutant with <i>skn-1</i>, but not <i>hsf-1</i> RNAi results in a developmental arrest phenotype. (D) Analysis of gene expression via Nanostring shows an increase in proteasome subunits in the <i>rpn-10</i> mutant compared to wild-type animals. The increase in proteasome subunits depends on <i>skn-1</i> but not <i>elt-2</i>, and the activation of <i>skn-1</i> with <i>wdr-23</i> RNAi fails to activate subunit expression. (E) In parallel Nanostring studies, the <i>rpn-10</i> mutant also shows a small <i>skn-1</i> dependent, but not <i>elt-2</i> dependent, increase in the expression of the oxidative stress response genes, <i>gcs-1</i>, <i>gst-4</i>, and <i>gst-5</i>. In contrast, <i>wdr-23</i> RNAi produces a marked increase in the expression of these genes (mean expression level of <i>gcs-1–</i>4,326, <i>gst-4–</i>24,714, and <i>gst-5–</i>4,982). For details of statistical testing for Panel D and Panel E see <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005823#pgen.1005823.s005\" target=\"_blank\">S5 Table</a>.</p>", "links"=>[], "tags"=>["lysosome", "SKN", "proteasome dysfunction", "Caenorhabditis elegans proteasome subunit", "atg", "Graded Proteasome Dysfunction", "ELT", "rpn", "protein", "pathway", "RPN", "Caenorhabditis elegans Activates", "GFP", "genes encoding proteasome subunits"], "article_id"=>2616796, "categories"=>["Biophysics", "Biochemistry", "Microbiology", "Cell Biology", "Genetics", "Molecular Biology", "Neuroscience", "Immunology", "Biological Sciences not elsewhere classified", "Developmental Biology", "Infectious Diseases", "Plant Biology", "Computational Biology"], "users"=>["Scott A. Keith", "Sarah K. Maddux", "Yayu Zhong", "Meghna N. Chinchankar", "Annabel A. Ferguson", "Arjumand Ghazi", "Alfred L. Fisher"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005823.g005", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_i_skn_1_i_is_required_for_the_viability_of_the_i_rpn_10_i_mutant_and_controls_the_expression_of_proteasome_subunits_/2616796", "title"=>"<i>skn-1</i> is required for the viability of the <i>rpn-10</i> mutant and controls the expression of proteasome subunits.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2016-02-01 00:11:10"}
  • {"files"=>["https://ndownloader.figshare.com/files/4266925"], "description"=>"<p>(A) The <i>rpn-10</i> mutant animals show increased expression of <i>hsf-1</i> but not <i>skn-1</i> compared to wild-type worms as shown by Nanostring analysis (N = 5 independent samples for N2 and 6 independent samples for <i>rpn-10</i>, *** represents p = 0.03). (B and C) The <i>rpn-10</i> mutant animals show increased expression of the <i>gst-4p</i>::<i>GFP</i> reporter compared to wild-type animals, in the absence of exogenous oxidative stress, with increased expression seen mainly in the intestine and hypodermis (n = 15 for WT and <i>rpn-10</i>, *** represents p<0.05 by <i>t</i>-test). (D) When Nanostring is used to measure the expression of <i>hsp-12</i>.<i>6</i>, <i>hsp-16</i>.<i>2</i>, and <i>hsp-70</i> in the <i>rpn-10</i> mutant and wild-type animals, the <i>rpn-10</i> mutants do not show up-regulation of the heat shock response in the absence of external stressors (p>0.2 for all three genes). In contrast, the <i>rpn-10</i> mutant animals show increased expression of the <i>hsp-16</i>.<i>2p</i>::<i>GFP</i> (E and F) and of the <i>hsp-70p</i>::<i>GFP</i> (G and H) reporters during the recovery from a one hour heat shock. In panel F, n = 10 for all genotypes and conditions and p<0.01 for WT and <i>rpn-10</i> post-heat shock. In panel H, n = 10 for all genotypes and conditions and p<0.05 for WT and <i>rpn-10</i> post-heat shock.</p>", "links"=>[], "tags"=>["lysosome", "SKN", "proteasome dysfunction", "Caenorhabditis elegans proteasome subunit", "atg", "Graded Proteasome Dysfunction", "ELT", "rpn", "protein", "pathway", "RPN", "Caenorhabditis elegans Activates", "GFP", "genes encoding proteasome subunits"], "article_id"=>2616733, "categories"=>["Biophysics", "Biochemistry", "Microbiology", "Cell Biology", "Genetics", "Molecular Biology", "Neuroscience", "Immunology", "Biological Sciences not elsewhere classified", "Developmental Biology", "Infectious Diseases", "Plant Biology", "Computational Biology"], "users"=>["Scott A. Keith", "Sarah K. Maddux", "Yayu Zhong", "Meghna N. Chinchankar", "Annabel A. Ferguson", "Arjumand Ghazi", "Alfred L. Fisher"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005823.g003", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/The_i_rpn_10_i_mutant_shows_enhanced_expression_of_oxidative_stress_and_heat_shock_response_genes_/2616733", "title"=>"The <i>rpn-10</i> mutant shows enhanced expression of oxidative stress and heat shock response genes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2016-02-01 00:11:10"}
  • {"files"=>["https://ndownloader.figshare.com/files/4223131", "https://ndownloader.figshare.com/files/4266802", "https://ndownloader.figshare.com/files/4266796", "https://ndownloader.figshare.com/files/4266793", "https://ndownloader.figshare.com/files/4266790", "https://ndownloader.figshare.com/files/4266784", "https://ndownloader.figshare.com/files/4266781", "https://ndownloader.figshare.com/files/4266778", "https://ndownloader.figshare.com/files/4266772", "https://ndownloader.figshare.com/files/4266769", "https://ndownloader.figshare.com/files/4266766", "https://ndownloader.figshare.com/files/4266757", "https://ndownloader.figshare.com/files/4266754", "https://ndownloader.figshare.com/files/4266748", "https://ndownloader.figshare.com/files/4266745", "https://ndownloader.figshare.com/files/4223134", "https://ndownloader.figshare.com/files/4266814"], "description"=>"<div><p>The maintenance of cellular proteins in a biologically active and structurally stable state is a vital endeavor involving multiple cellular pathways. One such pathway is the ubiquitin-proteasome system that represents a major route for protein degradation, and reductions in this pathway usually have adverse effects on the health of cells and tissues. Here, we demonstrate that loss-of-function mutants of the <i>Caenorhabditis elegans</i> proteasome subunit, RPN-10, exhibit moderate proteasome dysfunction and unexpectedly develop both increased longevity and enhanced resistance to multiple threats to the proteome, including heat, oxidative stress, and the presence of aggregation prone proteins. The <i>rpn-10</i> mutant animals survive through the activation of compensatory mechanisms regulated by the conserved SKN-1/Nrf2 and ELT-2/GATA transcription factors that mediate the increased expression of genes encoding proteasome subunits as well as those mediating oxidative- and heat-stress responses. Additionally, we find that the <i>rpn-10</i> mutant also shows enhanced activity of the autophagy-lysosome pathway as evidenced by increased expression of the multiple autophagy genes including <i>atg-16</i>.<i>2</i>, <i>lgg-1</i>, and <i>bec-1</i>, and also by an increase in GFP::LGG-1 puncta. Consistent with a critical role for this pathway, the enhanced resistance of the <i>rpn-10</i> mutant to aggregation prone proteins depends on autophagy genes <i>atg-13</i>, <i>atg-16</i>.<i>2</i>, and <i>prmt-1</i>. Furthermore, the <i>rpn-10</i> mutant is particularly sensitive to the inhibition of lysosome activity via either RNAi or chemical means. We also find that the <i>rpn-10</i> mutant shows a reduction in the numbers of intestinal lysosomes, and that the <i>elt-2</i> gene also plays a novel and vital role in controlling the production of functional lysosomes by the intestine. Overall, these experiments suggest that moderate proteasome dysfunction could be leveraged to improve protein homeostasis and organismal health and longevity, and that the <i>rpn-10</i> mutant provides a unique platform to explore these possibilities.</p></div>", "links"=>[], "tags"=>["lysosome", "SKN", "proteasome dysfunction", "Caenorhabditis elegans proteasome subunit", "atg", "Graded Proteasome Dysfunction", "ELT", "rpn", "protein", "pathway", "RPN", "Caenorhabditis elegans Activates", "GFP", "genes encoding proteasome subunits"], "article_id"=>2579029, "categories"=>["Biophysics", "Biochemistry", "Microbiology", "Cell Biology", "Genetics", "Molecular Biology", "Neuroscience", "Immunology", "Biological Sciences not elsewhere classified", "Developmental Biology", "Infectious Diseases", "Plant Biology", "Computational Biology"], "users"=>["Scott A. Keith", "Sarah K. Maddux", "Yayu Zhong", "Meghna N. Chinchankar", "Annabel A. Ferguson", "Arjumand Ghazi", "Alfred L. Fisher"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1005823.s001", "https://dx.doi.org/10.1371/journal.pgen.1005823.s016", "https://dx.doi.org/10.1371/journal.pgen.1005823.s015", "https://dx.doi.org/10.1371/journal.pgen.1005823.s014", "https://dx.doi.org/10.1371/journal.pgen.1005823.s013", "https://dx.doi.org/10.1371/journal.pgen.1005823.s012", "https://dx.doi.org/10.1371/journal.pgen.1005823.s011", "https://dx.doi.org/10.1371/journal.pgen.1005823.s010", "https://dx.doi.org/10.1371/journal.pgen.1005823.s009", "https://dx.doi.org/10.1371/journal.pgen.1005823.s008", "https://dx.doi.org/10.1371/journal.pgen.1005823.s007", "https://dx.doi.org/10.1371/journal.pgen.1005823.s006", "https://dx.doi.org/10.1371/journal.pgen.1005823.s005", "https://dx.doi.org/10.1371/journal.pgen.1005823.s004", "https://dx.doi.org/10.1371/journal.pgen.1005823.s003", "https://dx.doi.org/10.1371/journal.pgen.1005823.s002", "https://dx.doi.org/10.1371/journal.pgen.1005823.s017"], "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Graded_Proteasome_Dysfunction_in_i_Caenorhabditis_elegans_i_Activates_an_Adaptive_Response_Involving_the_Conserved_i_SKN_1_i_and_i_ELT_2_i_Transcription_Factors_and_the_Autophagy_Lysosome_Pathway/2579029", "title"=>"Graded Proteasome Dysfunction in <i>Caenorhabditis elegans</i> Activates an Adaptive Response Involving the Conserved <i>SKN-1</i> and <i>ELT-2</i> Transcription Factors and the Autophagy-Lysosome Pathway", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2016-02-01 00:11:10"}

PMC Usage Stats | Further Information

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  • {"unique-ip"=>"16", "full-text"=>"21", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"2"}
  • {"unique-ip"=>"16", "full-text"=>"20", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"9", "cited-by"=>"0", "year"=>"2019", "month"=>"3"}
  • {"unique-ip"=>"22", "full-text"=>"26", "pdf"=>"7", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"4"}
  • {"unique-ip"=>"19", "full-text"=>"22", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2019", "month"=>"5"}

Relative Metric

{"start_date"=>"2016-01-01T00:00:00Z", "end_date"=>"2016-12-31T00:00:00Z", "subject_areas"=>[]}
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