1BK21 FOUR KNU Creative BioResearch Group, School of Life Sciences, College of National Sciences, Kyungpook National University, Daegu 41566, 2Brain Science and Engineering Institute, Kyungpook National University, Daegu 41566, Korea
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Ribosomes are macromolecular complexes consisted of both proteins and RNAs. They are cellular factories for the translation of mRNAs into corresponding proteins (1, 2). In most eukaryotes, individual ribosomal proteins synthesized in the cytoplasm are reimported into the nucleus, while ribosomal RNA (rRNA) is synthesized in a nucleolus, a discrete compartment within the nucleus (3). The coordination between more than 200 assembly factors and many small nucleolar RNAs (snoRNAs) is essential for ribosome biogenesis and leads to the build-up of the 40S and 60S pre-ribosomal particles. The 40S particle contains distinct ribosomal proteins with 18S rRNA, whereas the 60S particle contains 28S, 5.8S, and 5S rRNA. Both subunits are exported to the cytoplasm for final maturation, and the 80S ribosome is eventually assembled from the 40S and 60S subunits to initiate protein synthesis (4). The ribosome biogenesis pathway requires the precise regulation of multiple steps, including transcription as well as protein assembly and transport. The transcriptional control of rRNA and ribosomal protein-encoding genes is the first rate-limiting step in biosynthesis. It is regulated by diverse pathways, such as PI3K/AKT/mTOR, RAS/RAF/MEK, p53, and Myc, which act as master regulators of cell proliferation (5-8). Subsequently, several regulatory factors engage in various steps during the successful maturation of pre-rRNA transcripts and ribosome assembly and export; these processes are tightly regulated by various post-translational modifications, including the small ubiquitin-related modifier (SUMO) pathway (9). Recent investigations utilizing biochemical and genome-wide analyses have significantly contributed toward our understanding of SUMO modification in ribosome synthesis and maturation; therefore, in the present review, we provide an overview of the newly discovered functions of SUMO in ribosome biogenesis.
SUMO is an evolutionarily conserved protein that plays important roles in diverse cellular processes, including DNA replication, transcription, translation, viral infection, stress response, and ribosome biogenesis (10-14). Humans have five genes that encode SUMO paralogs, SUMO-1 to SUMO-5, while yeast
Recent advances in molecular techniques and quantitative proteomics have revealed several interesting SUMO target proteins. Pioneer studies have been conducted in
Primary target proteins of SUMO are transcription factors and chromatin-associated proteins in eukaryotes (35, 36). It was initially thought that SUMO mainly would suppress gene transcription because it either blocked the function of transcription activators or facilitated the function of transcription repressors (37). However, recent investigations have uncovered its more diverse roles in co-transcriptional processes, including transcription activation and chromatin remodeling (35). In particular, SUMO is highly enriched in genes encoding ribosomal proteins and rRNA in human cells, and inhibition of SUMOylation leads to expression upregulation of these genes, implying that SUMO normally plays a role in limiting their expression (Fig. 2) (38). Human PIAS SUMO E3 ligases are indirectly involved in the repression of rRNA transcription by suppressing the expression of upstream binding factor and c-Myc, which are required for rRNA transcription (39). On the other hand, a study in
rRNA processing is essential for ribosome biogenesis. It is mediated by small nucleolar ribonucleoprotein complexes (snoRNPs) composed of snoRNAs and nucleolar proteins (46). snoRNAs are classified into two groups, box C/D snoRNAs responsible for 2’-
During ribosome biogenesis, 90S pre-ribosomal particles are established in the nucleolus and then split into 60S and 40S pre-ribosomes. These pre-ribosomal subunits are transported into the cytoplasm for final maturation (52). Human SENP3 is co-purified with PELP1, TEX10, WDR18, and LAS1L. SENP3-mediated control of SUMO conjugation level of PELP1 and LAS1L is essential for the maturation of rRNA and nucleolar export of 60S pre-ribosomal particles (53-55). SUMO can negatively affect conjugation of NEDD8, another ubiquitin-like protein, to human Rpl11, and facilitate the translocation of Rpl11 from nucleoli (56). Rps3, a DNA repair endonuclease, is also a substrate of the SUMO pathway that increases the stability of Rps3 protein (57). SUMOylation of Rpl22e is important for nucleoplasmic distribution of Rpl22 in
SUMOylation is known to play critical roles in ribosome biogenesis, and regulation of this modification is associated with gene expression, nuclear import, and assembly of ribosomal subunits. However, the ultimate and detailed functions of the SUMO pathway in ribosome establishment have remained unclear until recently. Here, we briefly summarize recent observations of how the SUMO pathway is involved in ribosome biogenesis. Several ribosomal proteins themselves and various factors required for ribosome assembly are substrates of SUMOylation. These SUMO modifications are tightly regulated by SUMO-specific proteases, leading to regulation of gene expression, localization, and function as well as proteolytic control of target proteins during ribosome maturation. Functionally healthy ribosomes are vital for cell survival, and several mutations in ribosomes or ribosome assembly factors have been found to be lethal (61, 62). Especially, specific defects in ribosome biogenesis or function could cause various clinical abnormalities, including skin and bone marrow failure syndromes such as X-linked dyskeratosis congenita and Schwachman-Diamond syndrome (63, 64). Thus, studying SUMO functions in ribosome biogenesis and activities might provide clue to develop new therapies and drug targets for human disorders of ribosome dysfunction.
This study was supported by a National Research Foundation of Korea (NRF) grant funded by the South Korean government (MSIT) (nos. 2020R1C1C1009367 and 2020R1A4A1018280) and Korean Environment Industry & Technology Institute (KEITI) through Core Technology Development Project for Environmental Diseases Prevention and Management funded by Korean Ministry of Environment (MOE) (no. 2022003310001).
The authors have no conflicting interests.