Tissue-Specific Impact of Autophagy Genes on the Ubiquitin–Proteasome System in C. elegans

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http://hdl.handle.net/10138/318466

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Jha, S.; Holmberg, C.I. Tissue-Specific Impact of Autophagy Genes on the Ubiquitin–Proteasome System in C. elegans. Cells 2020, 9, 1858.

Julkaisun nimi: Tissue-Specific Impact of Autophagy Genes on the Ubiquitin–Proteasome System in C. elegans
Tekijä: Jha, Sweta; Holmberg, Carina I.
Julkaisija: Multidisciplinary Digital Publishing Institute
Päiväys: 2020-08-08
URI: http://hdl.handle.net/10138/318466
Tiivistelmä: The ubiquitin&ndash;proteasome system (UPS) and the autophagy&ndash;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.


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