Rpl22 Loss Impairs the Development of B Lymphocytes by Activating a p53-Dependent Checkpoint

Abstract

While ribosomal proteins facilitate the ribosome’s core function of translation, emerging evidence suggests that some ribosomal proteins are also capable of performing tissue restricted functions either from within specialized ribosomes or from outside of the ribosome. In particular, we have previously demonstrated that germline ablation of the gene encoding ribosomal protein Rpl22 causes a selective and p53 dependent arrest of αβ T cell progenitors at the β-selection checkpoint. We have now identified a crucial role for Rpl22 during early B cell development. Germline ablation of Rpl22 results in a reduction in the absolute number of B-lineage progenitors in the bone marrow beginning at the pro-B cell stage. Although Rpl22-deficient proB cells are hyporesponsive to IL-7, a key cytokine required for early B cell development, the arrest of B cell development does not result from disrupted IL-7 signaling. Instead, p53 induction appears to be responsible for the developmental defects, as Rpl22-deficiency causes increased expression of p53 and activation of downstream p53 target genes and p53-deficiency rescues the defect in B cell development in Rpl22-deficient mice. Interestingly, the requirement for Rpl22 in the B cell lineage appears to be developmentally restricted, since Rpl22-deficient splenic B cells proliferate normally in response to antigen receptor and toll receptor stimuli and undergo normal class switch recombination. These results indicate that Rpl22 performs a critical, developmentally restricted role in supporting early B cell development by preventing p53-induction.

Rpl22 Loss Selectively Impairs αβ T Cell Development by Dysregulating Endoplasmic Reticulum Stress Signaling

“…Thus, it may be the abrupt transition from quiescence to rapid proliferation that sensitizes Rpl22-deficient αβ lineage progenitors to arrest. Consistent with this notion, we observe a similar arrest at the equivalent stage of B lymphoid development, where pre-B cell receptor signals induce a comparably abrupt transition to rapid proliferation (53). Nevertheless, we have not yet been able to test the causal relationship between proliferation and arrest, which could entail blunting the capacity of Rpl22-deficient αβ lineage progenitors to proliferate.…”

Regulatory Roles of Rpl22 in Hematopoiesis: An Old Dog with New Tricks

“…Despite the ubiquitous expression of Rpl22, its germline ablation does not result in embryonic lethality or gross abnormalities in mice, but does result in profound reductions in selected peripheral lymphocyte populations 98 . Indeed, Rpl22-deficient mice have striking decreases in splenic CD4 and CD8 T cells, and somewhat more modest reductions in splenic B2 cells and B1 B cells present in the peritoneal cavity 98,134 . Surprisingly, Rpl22-deficient peripheral B cells appear fully functional, as they are able to proliferate in response to mitogenic stimulation, upregulate activation markers, and undergo class switch recombination.…”

“…Surprisingly, Rpl22-deficient peripheral B cells appear fully functional, as they are able to proliferate in response to mitogenic stimulation, upregulate activation markers, and undergo class switch recombination. Initial studies reported that Rpl22-deficient T cells were unable to proliferate in response to TCR stimulation 98 ; however, this is likely to be due to the extensive homeostatic proliferation that occurs in Rpl22-deficient mice, which are lymphopenic because of limited thymic output 134 . While these studies do not rule out a role for Rpl22 in peripheral immune responses, they suggest that the predominant role of Rpl22 is likely to be in supporting normal lymphoid development.…”

“…While initial studies reported potential defects in B cell development in Rpl22-deficient mice 98,100 , it was only recently that the stages of B cell development impacted by the loss of Rpl22 were reported 134 . Rpl22-deficiency causes a mild reduction in pro-B cells that becomes more pronounced at the pre-B and immature B cell stages, demonstrating that Rpl22 is required for early B cell development.…”

Ribosomal Protein Rpl22 Controls the Dissemination of T-cell Lymphoma

“…Rpl22 is dispensable for ribosome biogenesis and global, cap-dependent translation; however, Rpl22 does play a critical, lineage-restricted role in supporting hematopoiesis (4, 5). Indeed, despite the ubiquitous expression of Rpl22, Rpl22-null mice are viable and fertile, with the only obvious defect being an exquisitely specific p53-dependent block in certain lymphoid subsets, including αβ lineage T cells (5, 6). The tissue-restricted nature of the developmental abnormalities caused by Rpl22-deficiency, clearly distinguish Rpl22 from other RPs, whose loss usually results in early lethality (3, 7).…”