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Review
. 2020 Jan 3;432(1):170-184.
doi: 10.1016/j.jmb.2019.06.001. Epub 2019 Jun 11.

Ribosome Abundance Control Via the Ubiquitin-Proteasome System and Autophagy

Heeseon An  1 , J Wade Harper  2
Affiliations
Review

Ribosome Abundance Control Via the Ubiquitin-Proteasome System and Autophagy

Heeseon An et al. J Mol Biol. .

Abstract

Ribosomes are central to the life of a cell, as they translate the genetic code into the amino acid language of proteins. Moreover, ribosomal abundance within the cell is coordinated with protein production required for cell function or processes such as cell division. As such, it is not surprising that these elegant machines are both highly regulated at the level of both their output of newly translated proteins but also at the level of ribosomal protein expression, ribosome assembly, and ribosome turnover. In this review, we focus on mechanisms that regulate ribosome abundance through both the ubiquitin-proteasome system and forms of autophagy referred to as "ribophagy." We discussed mechanisms employed in both yeast and mammalian cells, including the various machineries that are important for recognition and degradation of ribosomal components. In addition, we discussed controversies in the field and how the development of new approaches for examining flux through the proteasomal and autophagic systems in the context of a systematic inventory of ribosomal components is necessary to fully understand how ribosome abundance is controlled under various physiological conditions.

Keywords: autophagy; degradation; ribosome; ubiquitin.

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Conflict of interest statement

Declarations of interest: J.W.H. is a founder and board member of Rheostat Therapeutics and is a consultant for X-Chem, Inc.

Figures

Fig. 1.
Fig. 1.
Overview of ribosome assemblies and trafficking. (A) Size, composition, and cellular contribution of ribosomes in three domains of life. Ribosomal RNA constitutes 80% of total RNA in all three domains. However, the contribution of ribosomal proteins to the total proteome varies. Data for E. coli ribosomes, [25]. Data for S. cerevisiae, [89]. Data for H. sapiens was from analysis of the proteomic ruler data in [21, 27]. (B) Fundamentals of ribosome trafficking. Newly synthesized ribosomes travel from the cytosol to the nucleolus for pre-ribosomal complex formation before returning to the cytosol to complete the biogenesis process. In addition, fully assembled ribosomes dynamically move within the cytosol or to the ER membranes for translation of different pools of mRNAs [90].
Fig. 2.
Fig. 2.
Overview of pathways regulating ribosomal turnover by the ubiquitin-proteasome system and autophagy. Ribosomal assemblies and the abundance of individual ribosomal proteins can be controlled by both the ubiquitin system and autophagy. While the ubiquitin system generally controls turnover of individual ribosomal proteins, autophagy controls turnover of the entire ribosome. In yeast containing an extra copy of an individual chromosome (called a “disome”), excess individual ribosomal proteins expressed from the disome are degraded by the proteasome, although critical E3s have not been reported. Excess subunits generated from transcription and translational imbalances are thought to be ubiquitylated by the Tom1p E3 in yeast and the HUWE1 E3 in humans. During erythroid development, many ribosomal subunits are eliminated via the ubiquitin system via the UBE2O E3. The precise mechanisms underlying selectivity of UBE2O for individual ribosomal proteins are unclear. It is also unclear the extent to which UBE2O participates in degradation of excess ribosomal proteins in non-erythroid cells. Finally, various forms of cell stress and nutrient deprivation can lead to turnover of the entire ribosome via autophagy.
Fig. 3.
Fig. 3.
Overview of proposed ribophagy pathways in yeast and mammals. (A) During nutrient rich conditions, it has been reported that ribophagy in yeast is protected by the ubiquitylation of Rpl25 by the E3 ubiquitin ligase Ltn1. Upon starvation, the deubiquitylation enzyme Ubp3p-Bre5p removes the ubiquitin from Rpl25p, which subsequently leads to the selective sequestration of the 60S particle by autophagic membranes through an unknown mechanism. Ubp3p-Bre5p-dependent ribophagic flux is responsible for ~50% of the total ribophagic flux during starvation, but there is still significant flux (~50%) in Ubp3Δ cells, suggesting that there may be a pool of ribosomes that is differentially regulated. Whether or not an unknown receptor protein mediates the binding of 60S ribosomes to ATG8, and how the 40S assembly is selectively targeted is not known. (B) Ribosomes in mammals can be encapsulated in autophagosomes by three independent routes: 1) random sequestration during bulk autophagy, 2) by-stander flux during ER-phagy, and 3) receptor-mediated selective enrichment into autophagosomes. Quantitative methods and flux measurements are required to understand the contribution of each pathway under specific conditions.
Fig. 4.
Fig. 4.
Overview of conventional autophagy and a proposed “alternative” macro-autophagy pathway. In conventional macroautophagy (top), the VPS34 PI3P kinase complex containing BECLIN and ATG14, as well as the ULK1 kinase complex containing RB1CC1 and ATG13 are critical for initiation of ATG8 conjugation, which is catalyzed by the E1 enzyme ATG7 and its E3 complex composed of ATG5, ATG12, and ATG16. Lipidated ATG8 proteins (green) decorate growing autophagosomal double membrane structure, which capture cargo. These membranes close in a process whose efficiency is increased substantially by ATG8 lipidation. Closure precedes loading of STX17 (red) on to the autophagosomal membrane, which then facilitates fusion with a lysosome (orange). Degradation of the inner-autophagosomal membrane (IAM) by lysosomal enzymes is delayed by about 30 min in cells lacking ATG8 conjugation (Bottom).
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