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Review
. 2023 Jan 9;8(1):15.
doi: 10.1038/s41392-022-01285-4.

Ribosome biogenesis in disease: new players and therapeutic targets

Lijuan Jiao #  1 , Yuzhe Liu #  2 , Xi-Yong Yu #  3 , Xiangbin Pan #  4   5 , Yu Zhang  1 , Junchu Tu  1 , Yao-Hua Song  6   7 , Yangxin Li  8
Affiliations
Review

Ribosome biogenesis in disease: new players and therapeutic targets

Lijuan Jiao et al. Signal Transduct Target Ther. .

Abstract

The ribosome is a multi-unit complex that translates mRNA into protein. Ribosome biogenesis is the process that generates ribosomes and plays an essential role in cell proliferation, differentiation, apoptosis, development, and transformation. The mTORC1, Myc, and noncoding RNA signaling pathways are the primary mediators that work jointly with RNA polymerases and ribosome proteins to control ribosome biogenesis and protein synthesis. Activation of mTORC1 is required for normal fetal growth and development and tissue regeneration after birth. Myc is implicated in cancer development by enhancing RNA Pol II activity, leading to uncontrolled cancer cell growth. The deregulation of noncoding RNAs such as microRNAs, long noncoding RNAs, and circular RNAs is involved in developing blood, neurodegenerative diseases, and atherosclerosis. We review the similarities and differences between eukaryotic and bacterial ribosomes and the molecular mechanism of ribosome-targeting antibiotics and bacterial resistance. We also review the most recent findings of ribosome dysfunction in COVID-19 and other conditions and discuss the consequences of ribosome frameshifting, ribosome-stalling, and ribosome-collision. We summarize the role of ribosome biogenesis in the development of various diseases. Furthermore, we review the current clinical trials, prospective vaccines for COVID-19, and therapies targeting ribosome biogenesis in cancer, cardiovascular disease, aging, and neurodegenerative disease.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Schematic of ribosome biogenesis. a Eukaryotic ribosome biogenesis is a highly orchestrated process involving RNA Pol I, Pol II, and Pol III, which are responsible for transcribing rDNA to rRNA, producing 47S pre-rRNA in the nucleolus. The 4 rRNAs then assemble together with RPs to form a small ribosomal subunit (40S) and a large ribosomal subunit (60S). After assembly, the ribosome complex is exported from the nucleolus to the cytoplasm to form mature ribosomes for protein synthesis. b Bacterial ribosome biogenesis starts with the transcription of the precursors of 23S, 16S, and 5S rRNAs, and some tRNAs in the cytoplasm. The rRNAs then assemble with RPs to form a 30S small subunit and a 50S large subunit. After assembly, the ribosome complex forms mature ribosomes for protein synthesis. RP ribosome protein, RNA pol Ι/II/III RNA polymerase Ι/II/III, RNAP RNA polymerase, rDNA ribosomal DNA, rRNA, ribosomal RNA, tRNA transfer RNA
Fig. 2
Fig. 2
mTORC1 and ribosome biogenesis. Through phosphorylation, mTORC1 activates S6K1, which enhances rDNA transcription. mTORC1phosphorylates RPS6 to promote the synthesis of ribosomal 40S subunits, actively regulates the formation of RPS10 and RPL26, and promotes the initiation and elongation of mRNA through eIF4E and eIF2α, respectively. mTORC1 also phosphorylates and inactivates 4E-BPs to induce translation initiation. The RP assembly factor Urb1 is a downstream target of mTORC1 signaling. mTORC1 inhibits the binding of LARP1 and PABPC1 to promote mRNA translation and protein synthesis. mTORC1 mammalian target of rapamycin C1, rDNA ribosomal DNA, S6K1 S6 kinase 1, 4E-BP 4E-binding protein
Fig. 3
Fig. 3
Myc regulates ribosome biogenesis. Myc directly regulates rRNA processing, ribosome assembly, translocation from the nucleus to the cytoplasm, and the early steps of mRNA translation. Myc upregulates the transcriptional levels of these factors by recruiting cofactors and remodeling chromatin structure. Myc promotes RNA Pol I-mediated rDNA transcription by binding to UBF and SL1. After transcription, the 47S pre-rRNA is processed into mature 5.8S, 18S, and 28S rRNA. The Myc–STP5/SEC complex stimulates rRNA processing and transcription of RPS and RPL for export in an RNA Pol II-dependent manner. Myc binds transcription factor IIIB (TFIIIB) and activates the transcription of 5S rRNA and tRNA mediated by RNA Pol III. Finally, Myc stimulates RP synthesis through these RNA Pol I–III pathways. Myc myelocytomatosis oncogene, SL1 selectivity factor 1, TFIIIB transcription factor IIIB, UBF upstream binding factor
Fig. 4
Fig. 4
ncRNA and ribosome biogenesis. a There is a strong link between miRNA and ribosome biogenesis. miR-424-5p is elevated and targets the RNA Pol I pre-priming complex factors POLR1A and UBTF, which in turn downregulate mature rRNA levels. miR-20a, miR-194, and miR-206 inhibit Ncl expression by binding to the 3’UTR of Ncl, thereby affecting the subsequent splicing and processing of 47S pre-RNA. miR-595 inhibits ribosome biogenesis by reducing the expression of RPL27A and the synthesis of the mature 60S subunit. b Increased expression of lncRNA inhibits rDNA transcription through modification of rDNA chromatin, resulting in reduced pre-rRNA levels, mature rRNA levels, and overall translation. c circRNA recruits the 40S ribosomal subunit and initiates mRNA translation and protein synthesis. lncRNA long noncoding RNA, Ncl nucleolin, rDNA ribosomal RNA, pol Ι RNA polymerase Ι
Fig. 5
Fig. 5
a SARS-CoV-2 regulates ribosome biogenesis in host cells through multiple pathways. Nsp1 is used by the SARS-CoV-2 virus to ensure its own replication and spread in the human host. The 5’UTR of viral Nsp1 is a key factor in directing ribosomes to viral transcripts and blocking host cell mRNA translation. Nsp1 blocks host mRNA translation and enhance the synthesis of viral proteins. Nsp1 alters the balance between viral and host cellular mRNAs through the cleavage of host mRNAs, leading to the degradation of host mRNAs by cellular nucleases. b Nsp1 acts as a gatekeeper to help SARS-CoV-2 evasion. Early in infection, Nsp1 binds to the 40S subunit with the carboxy-terminal domain of Nsp1. The viral mRNA transcript forms a translation initiation complex with the 40S-Nsp1 complex in its 5’UTR SL1. The carboxy-terminal domain of Nsp1 is removed to open the ribosome biogenesis channel for viral mRNA. The translation initiation, elongation, and termination further proceed. Upon termination, the viral mRNA is released, and the Nsp1 carboxy terminus refolds to prevent any de novo translation of cellular mRNA. c Mechanisms of bacterial resistance. Reducing the concentration of the harmful drug in the bacterium by decreasing the permeability of the bacterial outer membrane. The antimicrobial substance in the bacterial cell is removed by the efflux pumps. Mutation or modification of the target structure to reduce the affinity for antibiotics. Enzymatic degradation of antibiotics. Nsp1 nonstructural protein 1
Fig. 6
Fig. 6. Ribosomes and CVD.
a (i) Ribosome dysfunction and cardiac hypertrophy. Increased UBF activity and abnormal activation of RNA Pol I and S6K1 induce cardiac hypertrophy. (ii) Ribosome dysfunction and MI. Downregulation of Ncl, rRNA, RPL9, and RPL26 leads to the failure of pre-rRNA processing, ultimately causing ribosome dysfunction and MI. b Ribosomes and atherosclerosis. Left: The over-activation of ribosome biogenesis results in abnormal proliferation of VSMCs and atherosclerosis. The expression of BOP1 and PES1 is increased in atherosclerotic patients, and both promote rRNA maturation by promoting pre-rRNA splicing and ribosome biogenesis. Right: RPL13 inhibits macrophage-induced inflammation and atherosclerosis. A high-fat diet promotes atherosclerosis in ApoE−/− mice, accompanied by higher levels of inflammatory cytokines. RPL13 inhibits the inflammatory response by inhibiting the translation of inflammatory genes such as CCL22, CXCL13a, and CCR3. BOP1 blocking of proliferation 1, PES1 pescadillo homolog 1
Fig. 7
Fig. 7
a Ribosome-stalling/collision/ribosome dysfunction and aging. The primary clearance pathway for ribosome collisions is the degradation of nascent peptides through ribosomal quality control (RQC). RQC decreases with age, and ribosome-stalling/collision triggers ribosome dysfunction. As a result, ribosome dysfunction leads to increased nascent polypeptides and protein aggregation. b Ribosomes and the signaling pathway of cellular senescence. Cellular DNA damage can be induced by radiation or chemotherapy, which activates p53-dependent stress responses and cause cellular senescence. SIRT1, a member of the longevity protein family, directly affects the activity of key proteins in the senescence pathway through deacetylating transcription factors. Moreover, SIRT1 recruits methylation enzymes to affect ribosome biogenesis by regulating chromatin remodeling, and abnormal ribosome biogenesis can directly affect p53 and telomerase activity to accelerate cellular senescence. Genomic instability of rDNA causes cellular senescence, and SIRT7, a member of the longevity protein family, affects rDNA stability by interacting with chromatin remodeling factors and RNA polymerase. Ncl and SIRT7 interact with proteins, and Ncl binding to telomeric reverse transcriptase affects ribosome biogenesis. Ac acetylation, CDK cyclin-dependent kinases, Me methylation, Ncl nucleolin, p phosphorylation, rDNA ribosomal DNA, RNA pol Ι RNA polymerase Ι
Fig. 8
Fig. 8. Ribosome and human diseases.
Abnormally active ribosome biogenesis is critical for cancer cell growth. The oncogene Myc upregulates rDNA transcription, activates RNA pol I-mediated 47S pre-rRNA synthesis, and induces the expression of RPL14 and RPL28 to stimulate ribosome biogenesis. In addition, Ncl enables cancer cells to differentiate and grow indefinitely by increasing the RNA Pol I activity. Blood diseases are associated with abnormal expression of RPs. RPL5/11 and RPS7/24 dysfunction and mutations in RPS19 activate p53, leading to a decline or even disappearance of erythroid cells, increasing the risk of malignant transformation. Ribosome dysfunction disrupts neuronal and glial homeostasis. Abnormal rDNA transcription affects the subsequent processing of 47S pre-rRNA into mature 5.8S, 18S, and 28S rRNA, disrupting rRNA synthesis and nucleolar integrity, and ultimately inducing neuronal cell death. Myc myelocytomatosis oncogene, Ncl nucleolin, rDNA ribosomal DNA, rRNA ribosomal RNA, RNA pol Ι RNA polymerase Ι
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References

    1. Djumagulov M, et al. Accuracy mechanism of eukaryotic ribosome translocation. Nature. 2021;600:543–546. doi: 10.1038/s41586-021-04131-9. - DOI - PMC - PubMed
    1. Lv K, et al. HectD1 controls hematopoietic stem cell regeneration by coordinating ribosome assembly and protein synthesis. Cell Stem Cell. 2021;28:1275–1290. doi: 10.1016/j.stem.2021.02.008. - DOI - PMC - PubMed
    1. Fan Y, et al. Phosphoproteomic analysis of neonatal regenerative myocardium revealed important roles of checkpoint kinase 1 via activating mammalian target of rapamycin C1/ribosomal protein S6 kinase b-1 pathway. Circulation. 2020;141:1554–1569. doi: 10.1161/CIRCULATIONAHA.119.040747. - DOI - PubMed
    1. Domitrovic T, Moreira MH, Carneiro RL, Ribeiro-Alves M, Palhano FL. Natural variation of the cardiac transcriptome in humans. RNA Biol. 2021;18:1374–1381. doi: 10.1080/15476286.2020.1857508. - DOI - PMC - PubMed
    1. Prakash V, et al. Ribosome biogenesis during cell cycle arrest fuels EMT in development and disease. Nat. Commun. 2019;10:2110. doi: 10.1038/s41467-019-10100-8. - DOI - PMC - PubMed

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