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Review
. 2022 Mar 14;18(6):2497-2514.
doi: 10.7150/ijbs.70955. eCollection 2022.

Eukaryotic ribosome quality control system: a potential therapeutic target for human diseases

Peng-Yue Zhao  1   2 , Ren-Qi Yao  1   3 , Zi-Cheng Zhang  4 , Sheng-Yu Zhu  2 , Yu-Xuan Li  2 , Chao Ren  1   5 , Xiao-Hui Du  2 , Yong-Ming Yao  1
Affiliations
Review

Eukaryotic ribosome quality control system: a potential therapeutic target for human diseases

Peng-Yue Zhao et al. Int J Biol Sci. .

Abstract

Protein homeostasis is well accepted as the prerequisite for proper operation of various life activities. As the main apparatus of protein translation, ribosomes play an indispensable role in the maintenance of protein homeostasis. Nevertheless, upon stimulation of various internal and external factors, malfunction of ribosomes may be evident with the excessive production of aberrant proteins, accumulation of which can result in deleterious effects on cellular fate and even cell death. Ribosomopathies are characterized as a series of diseases caused by abnormalities of ribosomal compositions and functions. Correspondingly, cell evolves several ribosome quality control mechanisms in maintaining the quantity and quality of intracellular ribosomes, namely ribosome quality control system (RQCS). Of note, RQCS can tightly monitor the entire process from ribosome biogenesis to its degradation, with the capacity of coping with ribosomal dysfunction, including misassembled ribosomes and incorrectly synthesized ribosomal proteins. In the current literature review, we mainly introduce the RQCS and elaborate on the underlying pathogenesis of several ribosomopathies. With the in-depth understanding of ribosomal dysfunction and molecular basis of RQCS, therapeutic strategy by specifically targeting RQCS remains a promising option in treating patients with ribosomopathies and other ribosome-associated human diseases.

Keywords: Human diseases; Ribophagy; Ribosome; Ribosome quality control; Ribosomopathy.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
The timeline diagram of major events in the discovery of RQCS. Abbreviation: TRAMP: TRf4/5-Air1/2-Mtr4 polyadenylation; RQC: ribosome quality control; ERISQ: excess ribosomal protein quality control; NUFIP-1: nuclear fragile X mental retardation-interacting protein 1.
Figure 2
Figure 2
The biogenesis and maturation of ribosomes. A: The biogenesis of ribosomes. In the nucleolus, ribosomal proteins firstly are combined with pre-ribosome RNAs (pre-rRNA) to form pre-60S and pre-40S. This process is regulated by multiple molecules and dedicated chaperones. These essential biogenesis factors include Ifh1, Utp22, U3-snoRNP, UTP-A, UTP-B, and UTP-C. In addition to above mentioned molecules, a number of complexes are manifested to play roles in the surveillance and turnover of misassembled preribosomes as well, such as the TRAMP complex and exosome complex of exonucleases. B: The maturation of ribosomes. Following synthesis of ribosomal subunit precursors in the nucleus, they need to enter the cytoplasm via the nuclear pore prior to combining with RPs to complete the maturation process. Dedicated chaperones specifically transport RPs to ensure the successful implementation of this process. The dedicated chaperones in the biogenesis of 60S LSU include Rrb1, Sqt1, Acl4, and Bcp1. While the dedicated chaperones Fap7, Nap1, Yar1, and Trs4 are involved in the maturation of 40S SSU. Abbreviation: Ifh1: interacts with forkhead 1; Utp22: U3 small nucleolar RNA-associated protein 22; UTP: U3 small nucleolar ribonucleoprotein particles; TRAMP: TRf4/5-Air1/2-Mtr4 polyadenylation; RPs: ribosomal proteins; LSU: the 60S large subunit; SSU: the 40S small subunit.
Figure 3
Figure 3
Ribosome recycle. Under stress, adjacent ribosomes performed protein translational function may collide. ZNF598 and RACK1 can identify colliding ribosomes, and recruit RQC complexes to split the colliding ribosomes. The splitting mRNA strands enter the NGD degradation pathway; the splitting large ribosomal subunits are specifically recognized by Ltn1 and Rqc2, while the semi-synthetic polypeptide chain is labeled by ubiquitinated proteins and then degraded into amino acids under the action of Cdc48, in terms of RQC process. A part of the splitting small ribosomal subunit is directly degraded by lysosomes (blockade with G3BP1-family-USP10), but another part that escapes lysosomal degradation recombines with the large ribosomal subunits and enters into the ribosomal recycle to perform protein translation functions. Abbreviation: RACK1: receptor for activated C kinase 1; RQC: ribosome quality control; NGD: no-go decay.
Figure 4
Figure 4
The degradation of excessive or non-functional ribosome proteins and rRNA. A: Ribosomes are assembled by rRNA and RPs following strict proportion. If certain stimuli impair ribosome synthesis process, RPs or rRNA will be overproduced disproportionately. B: The excessive or non-functional rRNA degradation pathways include Dim1p pathway, nuclear exosome pathway, TRAMP pathway, and NRD pathway. C: The excessive RPs degradation pathways include directly proteasomal degradation pathway, ERISQ pathway, and UBE2O pathway. Abbreviation: RPs: ribosomal proteins; TRAMP: TRf4/5-Air1/2-Mtr4 polyadenylation; NRD: nonfunctional rRNA decay; ERISQ: excess ribosomal protein quality control; UBE2O: ubiquitin conjugating enzyme E2O.
Figure 5
Figure 5
The autophagy of ribosomes. Ribosomes can be degraded by four autophagic pathways. 1) Macrophagy. Ribosomes are non-selectively wrapped by autophagosomes, and then fused with lysosomes to form autophagic lysosomes for degradation. 2) Ribophagy. The ribophagy receptor NUFIP-1 specifically recognizes the large ribosomal subunits under the help of ZNHIT3, and then binds to the LC-3B on the autophagosome membrane to complete the next process, however, the precise mechanism for degrading small ribosomal subunit remains to be elucidated. 3) Bystander autophagy pathway. When other selectively organelle autophagy occurs, such as mitochondrial autophagy, endoplasmic reticulum autophagy, etc., ribosomes can be engulfed and degraded incidentally. 4) RNautophagy. rRNA directly enters the lysosome for degradation through the protein receptor LAMP2C and SIDT2 (with the assistance of ARM) on the lysosomal membrane. Abbreviation: NUFIP-1: nuclear fragile X mental retardation-interacting protein 1; ZNHIT3: Zinc finger HIT domain containing protein 3; LAMP2C: lysosomal associated membrane protein 2C; SIDT2: SID-1 transmembrane family member 2; ARM: arginine-rich motif.
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