RPL12 is a Conserved Ribophagy Receptor

Cell Biology Biochemistry Life Sciences
ribophagy RPL12 cellular homeostasis autophagy receptor ribosome metabolism

Academic Background

Ribophagy is a selective autophagy process responsible for regulating the degradation and turnover of ribosomes. Ribosomes are the core machinery for protein synthesis in cells, and their synthesis and degradation are crucial for cellular adaptation to environmental changes, such as nutrient deprivation. Under nutrient-rich conditions, ribosome synthesis increases to support cell growth and proliferation, while under nutrient deprivation, ribosome degradation accelerates, releasing amino acids and nucleotides essential for cell survival. Although NUFIP1 has been identified as a ribophagy receptor in mammals, its homologues are absent in yeast and nematodes, suggesting the existence of alternative ribophagy receptors in these organisms.

This study aims to explore the conserved mechanisms of ribophagy, particularly in model organisms such as yeast, nematodes, and fruit flies. The research team discovered that the ribosomal large subunit protein RPL12 functions as a conserved ribophagy receptor across multiple species and revealed its critical role in cell survival, development, and aging.

Source of the Paper

The paper was co-authored by Yuting Chen, Jiaxin Hu, Pengwei Zhao, and others from institutions including Tianjin University, Zhejiang University, and University of Chinese Academy of Sciences. It was published in March 2025 in the journal Nature Cell Biology, with the title “RPL12 is a conserved ribophagy receptor.” The DOI of the paper is 10.1038/s41556-024-01598-2.

Research Process and Results

1. Direct Interaction of RPL12 with ATG8 and ATG11

The research team first identified, through bioinformatics analysis, the absence of NUFIP1 homologues in yeast and nematodes, suggesting the existence of alternative ribophagy receptors in these organisms. Using in vitro pull-down assays and yeast two-hybrid experiments, the team found that RPL12 directly interacts with the autophagy-related proteins ATG8 and ATG11. Further point mutation experiments revealed that the 3rd proline (P3) and the 21st glutamic acid (E21) of RPL12 are critical for its binding to ATG8.

2. Ribophagy Function of RPL12 in Yeast

To validate the role of RPL12 in ribophagy, the research team conducted a series of experiments in yeast models. By knocking out RPL12 or introducing the P3N-E21L mutation, the team found that disruption of the RPL12–ATG8 interaction significantly reduced the degradation of ribosomal proteins and rRNA. Additionally, ATG1-mediated phosphorylation of RPL12 enhanced its binding to ATG11, thereby triggering ribophagy under nutrient deprivation.

3. Conserved Function of RPL12 in Nematodes

The research team further validated the ribophagy function of RPL12 in nematodes. Through in vitro pull-down assays and co-immunoprecipitation experiments, the team found that the nematode homologue of RPL12, RPL-12, directly binds to the ATG8 homologue LGG-1, while the P3N-E21L mutation disrupted this interaction. Under nutrient deprivation, the degradation of ribosomal proteins and rRNA was significantly reduced in RPL-12 mutants, indicating that RPL-12 also functions as a ribophagy receptor in nematodes.

4. Ribophagy Function of RPL12 in Fruit Flies

In fruit fly models, the research team introduced the P3N-E21L mutation in RPL12 using CRISPR-Cas9 technology and found that the mutation significantly inhibited starvation-induced ribophagy. Moreover, RPL12 mutants exhibited increased sensitivity to starvation and pathogen infection, significantly shortened lifespans, and reduced motor abilities, highlighting the critical role of RPL12 in survival, development, and aging in fruit flies.

5. Ribophagy Function of RPL12 in Mammalian Cells

Finally, the research team validated the ribophagy function of RPL12 in mammalian cells. Through co-immunoprecipitation experiments, the team found that RPL12 directly binds to ATG8 homologues such as LC3C and GABARAP, while the P3N-E21L mutation disrupted this interaction. Under nutrient deprivation, the degradation of ribosomal proteins and rRNA was significantly reduced in RPL12 knockout or mutant cells, indicating that RPL12 also functions as a ribophagy receptor in mammals.

Research Conclusions

This study identified RPL12 as a conserved ribophagy receptor in yeast, nematodes, fruit flies, and mammals, regulating the degradation and turnover of ribosomes. Through direct interactions with ATG8 and ATG11, RPL12 triggers ribophagy under nutrient deprivation, thereby maintaining cellular survival, development, and aging balance. The study revealed the conserved function of RPL12 across multiple species, providing important insights into the molecular mechanisms of ribophagy.

Research Highlights

  1. Discovery of RPL12 as a Conserved Ribophagy Receptor: This study is the first to reveal the function of RPL12 as a ribophagy receptor in multiple species, filling the research gap in ribophagy receptors in yeast, nematodes, and fruit flies.
  2. Elucidation of the Interaction Mechanism Between RPL12 and ATG8/ATG11: Through point mutation and phosphorylation experiments, the research team clarified the interaction mechanism between RPL12 and ATG8/ATG11, providing important insights into the triggering mechanism of ribophagy.
  3. Critical Role of RPL12 in Cell Survival, Development, and Aging: The study found that RPL12 plays a key role in physiological processes such as nutrient deprivation, pathogen infection, and aging, offering potential therapeutic targets for related diseases.

Research Significance

This study not only revealed the conserved function of RPL12 as a ribophagy receptor but also provided a new perspective on how cells regulate ribosome turnover through autophagy. The findings are significant for understanding the molecular mechanisms of cellular adaptation to environmental changes and offer a theoretical foundation for developing therapeutic strategies targeting ribophagy-related diseases. Additionally, the conserved function of RPL12 across species provides new directions for research in evolutionary biology.

Through in-depth exploration, this study comprehensively revealed the function of RPL12 as a ribophagy receptor, providing significant theoretical support for the fields of cell biology and autophagy research.