Deletion of ribosomal paralogs Rpl39 and Rpl39l compromises cell proliferation via protein synthesis and mitochondrial activity.

Accumulating evidences suggest that the composition and functional roles of ribosomes are heterogeneous in cells, partly due to the temporal-spatial expression of paralogous ribosomal proteins (RPs), of which functional relationships remain largely unexplored. In mouse, the X chromosome-linked RPL39 and its male germline specific paralog RPL39L are thought to express mutually exclusively due to the meiotic sex chromosome inactivation, hinders the understanding of their functional relationships. In the present study, we investigated the expression and functional relations of Rpl39 and Rpl39l in a proliferative mouse cell line, in which both genes are expressed simultaneously, with the expression level of Rpl39 higher than that of Rpl39l. Disruption of Rpl39 via CRISPR/Cas9 method caused decreased cell proliferation, nascent protein synthesis and altered mitochondrial functions, whereas double mutations of Rpl39 and Rpl39l augmented these phenotypes, suggesting that both RPs contribute to the cellular physiology. Consistently, overexpression of Rpl39, Rpl39l or an alanine mutant of RPL39, rescued cell proliferation similarly in Rpl39::Rpl39l dual gene null cells. Deletion of Rpl39l induced compensatory expression of Rpl39, rendering the deleterious effects of Rpl39l mutation. Supporting this, Rpl39l mutation was more detrimental to cells under a low serum condition, under which the compensatory expression of Rpl39 was inhibited. Moreover, the low serum condition induced expression of both genes, suggesting that they possess stress responsive roles. Taken together, these data indicate that both RPL39 and RPL39L influence cell proliferation via protein synthesis and mitochondrial functions, suggesting a link between protein translation and cellular metabolism through these ribosomal protein paralogs.