Deficiency of ribosomal proteins reshapes the transcriptional and translational landscape in human cells. Issue 12 (8th February 2022) - Luan, Yizhao
Abstract: Human ribosomes have long been thought to be uniform factories with little regulatory function. Accumulating evidence emphasizes the heterogeneity of ribosomal protein (RP) expression in specific cellular functions and development. However, a systematic understanding of functional relevance of RPs is lacking. Here, we surveyed translational and transcriptional changes after individual knockdown of 75 RPs, 44 from the large subunit (60S) and 31 from the small subunit (40S), by Ribo-seq and RNA-seq analyses. Deficiency of individual RPs altered specific subsets of genes transcriptionally and translationally. RP genes were under cotranslational regulation upon ribosomal stress, and deficiency of the 60S RPs and the 40S RPs had opposite effects. RP deficiency altered the expression of genes related to eight major functional classes, including the cell cycle, cellular metabolism, signal transduction and development. 60S RP deficiency led to greater inhibitory effects on cell growth than did 40S RP deficiency, through P53 signaling. Particularly, we showed that eS8/RPS8 deficiency stimulated apoptosis while eL13/RPL13 or eL18/RPL18 deficiency promoted senescence. We also validated the phenotypic impacts of uL5/RPL11 and eL15/RPL15 deficiency on retina development and angiogenesis, respectively. Overall, our study provides a valuable resource for and novel insights into ribosome regulation in cellular activities, development and diseases. Lay Summary: Ribosomes are the main effector of the translational machinery to synthesize proteins. In this study, the authors characterized genome-wide transcriptional and translational changes after knocking-down 75 individual human ribosomal proteins (RPs). They revealed that deficiency of individual RPs perturbed expression of specific subsets of genes, enriched in eight major functional classes, such as cell cycle and development. RPs were subjected to co-translational regulation under ribosomal stress where deficiency of the 60S RPs and the 40S RPs had opposite effects on the two subunits. They also showed that RPS8 deficiency stimulated cellular apoptosis while RPL13 and RPL18 deficiency promoted cellular senescence. They further showed functional and regulatory roles of RPL11 and RPL15 in retina development and angiogenesis, respectively.