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Ribonuclease inhibitor 1 regulates erythropoiesis by controlling GATA1 translation
Vijaykumar Chennupati, … , Trang Hoang, Ramanjaneyulu Allam
Vijaykumar Chennupati, … , Trang Hoang, Ramanjaneyulu Allam
Published February 6, 2018
Citation Information: J Clin Invest. 2018;128(4):1597-1614. https://doi.org/10.1172/JCI94956.
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Research Article Development Hematology

Ribonuclease inhibitor 1 regulates erythropoiesis by controlling GATA1 translation

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Abstract

Ribosomal proteins (RP) regulate specific gene expression by selectively translating subsets of mRNAs. Indeed, in Diamond-Blackfan anemia and 5q– syndrome, mutations in RP genes lead to a specific defect in erythroid gene translation and cause anemia. Little is known about the molecular mechanisms of selective mRNA translation and involvement of ribosomal-associated factors in this process. Ribonuclease inhibitor 1 (RNH1) is a ubiquitously expressed protein that binds to and inhibits pancreatic-type ribonucleases. Here, we report that RNH1 binds to ribosomes and regulates erythropoiesis by controlling translation of the erythroid transcription factor GATA1. Rnh1-deficient mice die between embryonic days E8.5 and E10 due to impaired production of mature erythroid cells from progenitor cells. In Rnh1-deficient embryos, mRNA levels of Gata1 are normal, but GATA1 protein levels are decreased. At the molecular level, we found that RNH1 binds to the 40S subunit of ribosomes and facilitates polysome formation on Gata1 mRNA to confer transcript-specific translation. Further, RNH1 knockdown in human CD34+ progenitor cells decreased erythroid differentiation without affecting myelopoiesis. Our results reveal an unsuspected role for RNH1 in the control of GATA1 mRNA translation and erythropoiesis.

Authors

Vijaykumar Chennupati, Diogo F.T. Veiga, Kendle M. Maslowski, Nicola Andina, Aubry Tardivel, Eric Chi-Wang Yu, Martina Stilinovic, Cedric Simillion, Michel A. Duchosal, Manfredo Quadroni, Irene Roberts, Vijay G. Sankaran, H. Robson MacDonald, Nicolas Fasel, Anne Angelillo-Scherrer, Pascal Schneider, Trang Hoang, Ramanjaneyulu Allam

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Figure 10

RNH1 is present in ribosomal fraction and binds to small ribosomal subunit.

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RNH1 is present in ribosomal fraction and binds to small ribosomal subun...
(A) Western blot analysis of RNH1 and RPs in polysome-enriched pellet (P100) and the postpolysomal supernatant (S100) fraction prepared from K562 cytoplasmic extracts. Blots are representative of 3 independent experiments. (B) Western blot analysis of the distribution of RNH1 and RPs in sucrose gradient polysome profile fractions prepared from K562 cell lysates. Blots are representative of 3 independent experiments. (C) Polysome-enriched fractions were treated with high salt (0.5 M KCl). Distribution of RNH1 and RPs was analyzed by Western blot in sucrose gradient polysome profiles. Blots are representative of 3 independent experiments. (D) Polysome-enriched fractions were dissociated to 40S and 60S ribosomal subunits with puromycin. The distribution of RNH1 and RPs in pooled fractions was analyzed by Western blot in sucrose gradient polysome profiles. Blots are representative of 3 independent experiments. 18S and 28S rRNA from pooled 40S and 60S fractions were analyzed to check the purity of the 40S and 60S subunits, respectively.
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