Tissue-Specific Impact of Autophagy Genes on the Ubiquitin–Proteasome System in <i>C. elegans</i>
The ubiquitin–proteasome system (UPS) and the autophagy–lysosomal pathway (ALP) are the two main eukaryotic intracellular proteolytic systems involved in maintaining proteostasis. Several studies have reported on the interplay between the UPS and ALP, however it remains largely unknown how compromis...
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MDPI AG
2020-08-01
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| Online Access: | https://www.mdpi.com/2073-4409/9/8/1858 |
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| author | Sweta Jha Carina I. Holmberg |
| author_facet | Sweta Jha Carina I. Holmberg |
| author_sort | Sweta Jha |
| collection | DOAJ |
| description | The ubiquitin–proteasome system (UPS) and the autophagy–lysosomal pathway (ALP) are the two main eukaryotic intracellular proteolytic systems involved in maintaining proteostasis. Several studies have reported on the interplay between the UPS and ALP, however it remains largely unknown how compromised autophagy affects UPS function in vivo. Here, we have studied the crosstalk between the UPS and ALP by investigating the tissue-specific effect of autophagy genes on the UPS at an organismal level. Using transgenic <i>Caenorhabditis elegans</i> expressing fluorescent UPS reporters, we show that the downregulation of the autophagy genes <i>lgg-1</i> and <i>lgg-2 (ATG8/LC3/GABARAP)</i>, <i>bec-1 (BECLIN1)</i>, <i>atg-7 (ATG7)</i> and <i>epg-5</i> (mEPG5) by RNAi decreases proteasomal degradation, concomitant with the accumulation of polyubiquitinated proteasomal substrates in a tissue-specific manner. For some of these genes, the changes in proteasomal degradation occur without a detectable alteration in proteasome tissue expression levels. In addition, the <i>lgg-1</i> RNAi-induced reduction in proteasome activity in intestinal cells is not dependent on <i>sqst-1</i>/p62 accumulation. Our results illustrate that compromised autophagy can affect UPS in a tissue-specific manner, and demonstrate that UPS does not function as a direct compensatory mechanism in an animal. Further, a more profound understanding of the multilayered crosstalk between UPS and ALP can facilitate the development of therapeutic options for various disorders linked to dysfunction in proteostasis. |
| first_indexed | 2024-03-10T17:47:02Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T17:47:02Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-8f22136cff804ca1b0ce87474cd9b6fe2023-11-20T09:30:46ZengMDPI AGCells2073-44092020-08-0198185810.3390/cells9081858Tissue-Specific Impact of Autophagy Genes on the Ubiquitin–Proteasome System in <i>C. elegans</i>Sweta Jha0Carina I. Holmberg1Medicum, Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Haartmaninkatu 8, 00290 Helsinki, FinlandMedicum, Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Haartmaninkatu 8, 00290 Helsinki, FinlandThe ubiquitin–proteasome system (UPS) and the autophagy–lysosomal pathway (ALP) are the two main eukaryotic intracellular proteolytic systems involved in maintaining proteostasis. Several studies have reported on the interplay between the UPS and ALP, however it remains largely unknown how compromised autophagy affects UPS function in vivo. Here, we have studied the crosstalk between the UPS and ALP by investigating the tissue-specific effect of autophagy genes on the UPS at an organismal level. Using transgenic <i>Caenorhabditis elegans</i> expressing fluorescent UPS reporters, we show that the downregulation of the autophagy genes <i>lgg-1</i> and <i>lgg-2 (ATG8/LC3/GABARAP)</i>, <i>bec-1 (BECLIN1)</i>, <i>atg-7 (ATG7)</i> and <i>epg-5</i> (mEPG5) by RNAi decreases proteasomal degradation, concomitant with the accumulation of polyubiquitinated proteasomal substrates in a tissue-specific manner. For some of these genes, the changes in proteasomal degradation occur without a detectable alteration in proteasome tissue expression levels. In addition, the <i>lgg-1</i> RNAi-induced reduction in proteasome activity in intestinal cells is not dependent on <i>sqst-1</i>/p62 accumulation. Our results illustrate that compromised autophagy can affect UPS in a tissue-specific manner, and demonstrate that UPS does not function as a direct compensatory mechanism in an animal. Further, a more profound understanding of the multilayered crosstalk between UPS and ALP can facilitate the development of therapeutic options for various disorders linked to dysfunction in proteostasis.https://www.mdpi.com/2073-4409/9/8/1858autophagyubiquitin–proteasome systemcrosstalktissue specificity<i>C. elegans</i> |
| spellingShingle | Sweta Jha Carina I. Holmberg Tissue-Specific Impact of Autophagy Genes on the Ubiquitin–Proteasome System in <i>C. elegans</i> Cells autophagy ubiquitin–proteasome system crosstalk tissue specificity <i>C. elegans</i> |
| title | Tissue-Specific Impact of Autophagy Genes on the Ubiquitin–Proteasome System in <i>C. elegans</i> |
| title_full | Tissue-Specific Impact of Autophagy Genes on the Ubiquitin–Proteasome System in <i>C. elegans</i> |
| title_fullStr | Tissue-Specific Impact of Autophagy Genes on the Ubiquitin–Proteasome System in <i>C. elegans</i> |
| title_full_unstemmed | Tissue-Specific Impact of Autophagy Genes on the Ubiquitin–Proteasome System in <i>C. elegans</i> |
| title_short | Tissue-Specific Impact of Autophagy Genes on the Ubiquitin–Proteasome System in <i>C. elegans</i> |
| title_sort | tissue specific impact of autophagy genes on the ubiquitin proteasome system in i c elegans i |
| topic | autophagy ubiquitin–proteasome system crosstalk tissue specificity <i>C. elegans</i> |
| url | https://www.mdpi.com/2073-4409/9/8/1858 |
| work_keys_str_mv | AT swetajha tissuespecificimpactofautophagygenesontheubiquitinproteasomesysteminicelegansi AT carinaiholmberg tissuespecificimpactofautophagygenesontheubiquitinproteasomesysteminicelegansi |