Ribosome Ubiquitination

Ribosomes, the cellular machinery responsible for constructing proteins, are at the heart of most important biochemical processes. But even such crucial machinery can develop errors and need to be efficiently managed by the cell, a task primarily accomplished through Ribosome Ubiquitination (RU). RU is a fascinating process that plays an integral role in protein homeostasis and cellular health. This article aims to shed light on various aspects of ribosome ubiquitination, discussing its functions, mechanisms, and significance.

Functions of Ribosome Ubiquitination

Ubiquitination is a biological process where the post-translational modification of proteins occurs by attaching ubiquitin, a small protein, creating the so-called ubiquitin-protein conjugates. When ubiquitin gets attached to ribosomes, a process called ribosome ubiquitination is initiated. The multiplicity of these conjugates, created through the linkage of additional ubiquitin to the prior ones, forms a polyubiquitin chain serving different roles depending on their linkage sites. In the context of ribosomes, ubiquitination serves two main functions: ribosome-associated degradation and quality control. In degradation, ribosome ubiquitination collaborates with the proteasomes; complex cellular machines that degrade damaged or unnecessary proteins in an ATP-dependent manner. When the ribosome itself or the nascent polypeptide chains it produces are misfunctioning, ribosome ubiquitination tags them by adding ubiquitin molecules to signal proteasome for their degradation. Quality control, on the other hand, pertains to the early detection of ribosomal errors and prevention of malfunctioning protein synthesis. Ribosome ubiquitination plays a key role in this by identifying and tagging problematic ribosomes. It has also been observed to stall the translation process temporarily to allow for the repair of detected errors. Thus, ribosome ubiquitination serves as an integral component of ribosome-associated quality control (RQC) pathway, reducing the burden of protein misfolding and resulting pathologies.

Potential of Ribosome Ubiquitination as Therapeutic Intervention

Mechanistically, ribosome ubiquitination involves a cascade of events mediated through the coordinated actions of a series of ubiquitin-related enzymes, namely E1, E2, and E3. E1 activates ubiquitin in an ATP-dependent manner, E2 carries the activated ubiquitin, and E3 ligase catalyzes the final step of transferring ubiquitin from E2 to the target protein – in this case, the ribosome. Importantly, ubiquitin ligase Ltn1 has been recognized as one of the key E3s involved in ribosome ubiquitination in both yeast and mammals. Understanding ribosome ubiquitination is crucial as it is implicated in a wide range of important biological processes and diseases. For example, deficiencies or mutations in the components of ribosome ubiquitination machinery could lead to various neurodegenerative diseases and cancer. Therefore, it is a potential area of therapeutic intervention. Further, in recent years, exciting progress has been made in understanding the molecular mechanisms of ribosome ubiquitination, thanks to the application of highly sensitive mass spectrometry techniques and cryo-electron microscopy. However, many unanswered questions remain. For instance, what are the other E3 enzymes implicated in ribosome ubiquitination, and how do they recognize the target ribosomes? Do different ribosomal subunits have different susceptibility to ubiquitination?

Fig. 1 Ribosome Ubiquitination.¹

In conclusion, ribosome ubiquitination is a complex process with a significant impact on cellular health. Its role in protein degradation and quality control ensures protein homeostasis in cells, making it an interesting field for future research with far-reaching implications in understanding and treating diseases.

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Reference

1. Garzia, A., C. Meyer, and T. Tuschl. "The E3 ubiquitin ligase RNF10 modifies 40S ribosomal subunits of ribosomes compromised in translation. Cell Rep. 36, 109468." (2021).