TNF-mediated inflammation represses GATA1 and activates p38 MAP kinase in RPS19-deficient hematopoietic progenitors

Abstract

Key Points• GATA1 is downregulated in RPS19-deficient cells and zebrafish through upregulation of p53, TNF-a, and p38 MAPK.• Treatment of rps19-deficient zebrafish with the TNF-a inhibitor etanercept rescues their erythroid and developmental defects.Diamond-Blackfan anemia (DBA) is an inherited disorder characterized by defects in erythropoiesis, congenital abnormalities, and predisposition to cancer. Approximately 25% of DBA patients have a mutation in RPS19, which encodes a component of the 40S ribosomal subunit. Upregulation of p53 contributes to the pathogenesis of DBA, but the link between ribosomal protein mutations and erythropoietic defects is not well understood. We found that RPS19 deficiency in hematopoietic progenitor cells leads to decreased GATA1 expression in the erythroid progenitor population and p53-dependent upregulation of tumor necrosis factor-a (TNF-a) in nonerythroid cells. The decrease in GATA1 expression was mediated, at least in part, by activation of p38 MAPK in erythroid cells and rescued by inhibition of TNF-a or p53. The anemia phenotype in rps19-deficient zebrafish was reversed by treatment with the TNF-a inhibitor etanercept. Our data reveal that RPS19 deficiency leads to inflammation, p53-dependent increase in TNF-a, activation of p38 MAPK, and decreased GATA1 expression, suggesting a novel mechanism for the erythroid defects observed in DBA. (Blood. 2014;124(25):3791-3798)

Downregulation of GATA1 drives impaired hematopoiesis in primary myelofibrosis

“…Together, our results are reminiscent of the recent discovery that ribosomal gene mutations in Diamond-Blackfan anemia (DBA) lead to reduced GATA1 translation (17,18). Indeed, we observed that knockdown of RPS14 in SET2 cells led to a reduction in GATA1 protein (Supplemental Figure 13A).…”

The severe phenotype of Diamond-Blackfan anemia is modulated by heat shock protein 70

“…Other pathways may be involved and indeed, it has been recently shown in shRNA-RPS19 deficient erythroid progenitors that the activation of tumor necrosis factor a (TNF-a) through p38 MAPK phosphorylation could play a role in decreased GATA1 expression. 45 TNF-a acting via S100A8 and S100A9 proteins of the innate immune system has recently been shown to be involved in the 5q-MDSs. 46 We cannot exclude the possibility that 1 or more additional factors interacting with HSP70 depending on the specific RP mutated gene may be modulating the different phenotypes.…”

RNA Processing and Ribosome Biogenesis in Bone Marrow Failure Disorders

“…In patients bearing a RPS19 deficiency, the levels of GATA1 were found to be reduced in the erythroid progenitor population while p53 and TNFα expression were increased in the non-erythroid progenitors [18,20] . Inhibition of TNFα in a zebrafish model of RPS19-deficiency was able to rescue the observed anemia, suggesting TNFα expression has a significant role in the observed phenotype [20] .…”

“…In addition, an innate immune component has been observed. RP loss/reduction enhances the expression of innate immune genes including interferon and TNFα, which is known to contribute to the hematopoietic failure in RPS19 deficiency, likely through IRES-mediated translation [20] . Moreover, RP depletion affects the insulin signaling pathway [70] .…”

“…Interestingly, under the conditions of haploinsufficiencies of the RPs, the process of pre-rRNA maturation is altered resulting in an increasing pool of unassimilated RPs. These free RPs, including a complex consisting of 5S rRNA, RPL5 and RPL11, have been shown to associate with MDM2, the p53 ubiquitinase, and sequester it from p53, thus enhancing p53 protein stability [20,70] . In addition to this mechanism, other mechanisms, including DNA double-strand (ds) breaks due to replication stress and AMPK activation, due to ATP depletion, have been proposed to lead to increased p53 expression.…”