Abstract
Human ribosomes, made of around 80 ribosomal proteins (RPs) and four ribosomal RNAs, have long been thought as uniform passive protein-making factories with few regulatory functions. Recently, accumulating evidence showed heterogeneity of RP composition in ribosomes responsible for regulating gene expression in development and tumorigenesis. However, a comprehensive understanding of regulatory spectrum of RPs is unclear. In this study, we conducted a systematic survey of regulatory specificity of human RPs on global gene expression. We assessed deficiency of 75 RP, including 44 from the large subunit (60S) and 31 from the small subunit (40S), on gene translation and transcription via ribosomal profiling and RNA sequencing analysis. We showed that RP deficiency induced diverse expression changes, particularly at the translational level. RPs were subjected to co-translational regulation under ribosomal stress where deficiency of the 60S or the 40S RPs had distinguished effects on the two subunits. The gene ontology analysis revealed that RP deficiency perturbed expression of genes related to cell cycle, cellular metabolism, signal transduction and development. Deficiency of RPs from the 60S led to a greater repression effect on cell growth than that from the 40S by affecting P53 signaling and cell cycle pathways. To demonstrate functional specificity of RPs, we showed that RPS8 deficiency stimulated cellular apoptosis but RPL13 or RPL18 deficiency promoted cellular senescence. We also showed that RPL11 and RPL15 played important roles in retina development and angiogenesis, respectively. Overall, our study demonstrated a widespread regulatory role of RPs in controlling cellular activity and provided an important resource which offered novel insights into ribosome regulation in human diseases and cancer.
Competing Interest Statement
The authors have declared no competing interest.