Expanding Role of Ubiquitin in Translational Control

Abstract

The eukaryotic proteome has to be precisely regulated at multiple levels of gene expression, from transcription, translation, and degradation of RNA and protein to adjust to several cellular conditions. Particularly at the translational level, regulation is controlled by a variety of RNA binding proteins, translation and associated factors, numerous enzymes, and by post-translational modifications (PTM). Ubiquitination, a prominent PTM discovered as the signal for protein degradation, has newly emerged as a modulator of protein synthesis by controlling several processes in translation. Advances in proteomics and cryo-electron microscopy have identified ubiquitin modifications of several ribosomal proteins and provided numerous insights on how this modification affects ribosome structure and function. The variety of pathways and functions of translation controlled by ubiquitin are determined by the various enzymes involved in ubiquitin conjugation and removal, by the ubiquitin chain type used, by the target sites of ubiquitination, and by the physiologic signals triggering its accumulation. Current research is now elucidating multiple ubiquitin-mediated mechanisms of translational control, including ribosome biogenesis, ribosome degradation, ribosome-associated protein quality control (RQC), and redox control of translation by ubiquitin (RTU). This review discusses the central role of ubiquitin in modulating the dynamism of the cellular proteome and explores the molecular aspects responsible for the expanding puzzle of ubiquitin signals and functions in translation.Int. J. Mol. Sci. 2020, 21, 1151 2 of 24 initiation, elongation, and termination, with each being fundamental processes conserved across all organisms [20][21][22]. These steps require the proper binding of both RNA and protein factors, and regulation is often facilitated by the alteration of these binding patterns. As ribosomes are highly abundant and responsible for all protein synthesis within the cell, even minor changes to binding patterns could have a large impact on global protein production and cellular health, depending on which steps of translation are altered. Mutations and dysregulation of translational control can lead to a variety of diseases such as cancer, neurological disorders, bone marrow dysfunction and immunodeficiency, among others [23]. As translation is a core process in maintaining cellular function and health, dysfunctional regulation can have devastating results for the cell.Translational control does not occur in a universal manner across a single cell, but varies based on ribosomal subpopulations, with functions specific to cellular localization, transcript targeting, and signaling pathways [24,25]. These subpopulations are distinguishable by RNA and ribosomal protein composition [26,27], binding factors [28], intracellular localization [29,30], and post-translational modifications (PTM) [31]. These subpopulations have a differential capacity to bind and interact with both mRNA and protein factors required for active transla...

The ubiquitination-deubiquitination cycle on the ribosomal protein eS7A is crucial for efficient translation

“…Although it has been well established that ubiquitination of various ribosomal proteins is required for many critical aspects in translational control ( Dougherty et al., 2020 ), we have demonstrated for the first time that eS7 is cyclically ubiquitinated and deubiquitinated in the normal translation process. Our results reveal another layer of regulation for ribosome functions in which a ubiquitination-deubiquitination cycle plays a key role.…”

Ubiquitin and Ubiquitin-Like Proteins and Domains in Ribosome Production and Function: Chance or Necessity?

“…Ub functions as a reversible post-translational modifier of proteins to regulate many different cellular processes. Since its discovery, a role of Ub in proteasome-dependent protein degradation has been emphasized (e.g., [ 5 , 6 ]), but beyond this function, Ub participates in many other cellular processes, such as DNA repair, chromatin dynamics, cell cycle regulation, membrane and protein trafficking, endocytosis, autophagy, and transcriptional and translational control (reviewed in [ 7 , 8 , 9 ]). Accordingly, Ub is a very abundant cellular protein that is used to modify a large number of different proteins in yeast (>1000) and human (>9000) cells [ 10 , 11 ].…”

Structural impact of K63 ubiquitin on yeast translocating ribosomes under oxidative stress

“…Ubiquitination of ribosomes is a widespread process, which controls translation by facilitating ribosome biogenesis, degradation, and regulatory functions, such as translation quality control and translation reprogramming (9). K63 ubiquitin modifies ribosomes and regulates protein synthesis during cellular response to oxidative stress (10,11), however, the mechanism responsible for this regulation remains unknown.…”

“…One of the processes capable of regulating protein synthesis in response to stress involves posttranslational modification of ribosomes by ubiquitin. Ubiquitin, which is a prevalent protein modifier traditionally linked to protein degradation (8), modifies the ribosome and alters its function by inducing a variety of signaling pathways independent of proteasomal degradation (9). We have shown previously that, in response to oxidative stress, ribosomes are heavily modified by K63 ubiquitin, a chain of ubiquitin molecules linked at its lysine 63, and that this modification rapidly occurs because of redox regulation of selective ubiquitin enzymes (10).…”