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The ubiquitin-26S proteasome system and autophagy are two major protein degradation machineries encoded in all eukaryotic organisms. While the UPS is responsible for the turnover of short-lived and/or soluble misfolded proteins under normal growth conditions, the autophagy-lysosomal/vacuolar protein degradation machinery is activated under stress conditions to remove long-lived proteins in the forms of aggregates, either soluble or insoluble, in the cytoplasm and damaged organelles. Recent discoveries suggested an integrative function of these two seemly independent systems for maintaining the proteome homeostasis. One such integration is represented by their reciprocal degradation, in which the small 76-amino acid peptide, ubiquitin, plays an important role as the central signaling hub. In this review, we summarized the current knowledge about the activity control of proteasome and autophagosome at their structural organization, biophysical states, and turnover levels from yeast and mammals to plants. Through comprehensive literature studies, we presented puzzling questions that are awaiting to be solved and proposed exciting new research directions that may shed light on the molecular mechanisms underlying the biological function of protein degradation.
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Integrated proteasomal and lysosomal activity shape mTOR-regulated proteome remodeling
ABSTRACT The crucial growth regulator mTOR is suppressed during nutrient limitation, which reduces protein synthesis and activates the ubiquitin-proteasome system (UPS) and lysosomal degradation pathways. Whereas these pathways have been extensively studied individually, their integrated dynamics, including the interplay between protein synthesis and degradation, and the coordination between lysosomal and UPS pathways, remain underexplored. Here, we couple stable isotope pulse-labeling and mass spectrometry to quantify and kinetically model proteome dynamics following mTOR inhibition in cultured human cells. Using a combination of genetics and pharmacological inhibitors, we identify proteins strictly degraded by one pathway, those that undergo multimodal degradation, and others that can flexibly access the proteasome or lysosome subject to the availability of either. Our data resource, comprised of ∼5.2 million proteomic measurements, reveals that the UPS and lysosomal pathway operate with disparate kinetics, and highlights the rapid nature of lysosomal degradation. Additionally, we observe that cells coordinate the synthesis and degradation of translation initiation and elongation factors, leading to preferential synthesis from key classes of mRNA transcripts. Taken together, this work illuminates the complex, integrated pathways influencing proteostasis when mTOR is inhibited, provides a rich resource detailing the kinetics of protein synthesis and degradation, and establishes a robust methodology for measuring proteome dynamics on a per-protein basis in the context of cellular stress.
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- Award ID(s):
- 2046778
- PAR ID:
- 10686683
- Publisher / Repository:
- bioRxiv
- Date Published:
- Format(s):
- Medium: X
- Institution:
- bioRxiv
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript
- Posted Content:
- https://doi.org/10.1101/2024.07.20.603815
