Abstract
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 Caenorhabditis elegans expressing fluorescent UPS reporters, we show that the downregulation of the autophagy genes lgg-1 and lgg-2 (ATG8/LC3/GABARAP), bec-1 (BECLIN1), atg-7 (ATG7) and epg-5 (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 lgg-1 RNAi-induced reduction in proteasome activity in intestinal cells is not dependent on sqst-1/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.
Highlights
Protein homeostasis is a dynamic balance between protein biogenesis and degradation, and is essential for cell survival and growth
We reveal that the downregulation of certain autophagy genes that function at different autophagy–lysosomal pathway (ALP) steps elicits distinct tissue-specific effects on ubiquitin–proteasome system (UPS) in C. elegans, and that the observed changes in proteasomal degradation can occur either concomitant with, or without, a detectable change in proteasome tissue expression levels
The RNA Interference (RNAi)-sensitive rrf-3(pk1426) strain was exposed to various RNAi treatments, targeting the individual autophagy genes lgg-1, lgg-2, bec-1 (BECLIN 1), atg-7 (ATG7), rab-7 or epg-5 (Figure S1B), resulting in a clear downregulation of their corresponding mRNA levels (Figure S1C)
Summary
Protein homeostasis (proteostasis) is a dynamic balance between protein biogenesis and degradation, and is essential for cell survival and growth. The pool of intracellular and various extracellular proteins is constantly being replaced by newly synthesized proteins, and protein degradation must be selective and tightly regulated. The ubiquitin–proteasome system (UPS) and autophagy–lysosome pathway (ALP) are the two major intracellular proteolytic systems that mediate protein turnover. UPS is the main pathway responsible for the degradation of soluble and short-lived misfolded proteins, both in the cytosol and the nucleus. Proteasomal substrates are first polyubiquitinated via the action of three classes of enzymes: ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2) and ubiquitin ligases (E3), reviewed in [1,2]. The substrates are degraded by the evolutionarily conserved 26S proteasome, which consists of a central barrel-shaped core particle
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