Ribonuclease inhibitor 1 regulates erythropoiesis by controlling GATA1 translation.

Chennupati, Vijaykumar; Veiga, Diogo Ft; Maslowski, Kendle M; Andina, Nicola; Tardivel, Aubry Bernard Maurice; Yu, Eric Chi-Wang; Stilinovic, Martina; Simillion, Cedric; Duchosal, Michel A; Quadroni, Manfredo; Roberts, Irene; Sankaran, Vijay G; MacDonald, H Robson; Fasel, Nicolas; Angelillo, Anne; Schneider, Pascal; Hoang, Trang; Allam, Ramanjaneyulu (2018). Ribonuclease inhibitor 1 regulates erythropoiesis by controlling GATA1 translation. Journal of clinical investigation, 128(4), pp. 1597-1614. American Society for Clinical Investigation 10.1172/JCI94956

[img]
Preview
Text
AN_94956.3-20180321161135-covered-253bed37ca4c1ab43d105aefdf7b5536.pdf - Published Version
Available under License Publisher holds Copyright.

Download (17MB) | Preview

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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Haematology and Central Haematological Laboratory
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Hämatologie (Erwachsene)

UniBE Contributor:

Andina, Nicola; Tardivel, Aubry Bernard Maurice; Angelillo, Anne and Allam, Ramanjaneyulu

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0021-9738

Publisher:

American Society for Clinical Investigation

Language:

English

Submitter:

Pierrette Durand Lüthi

Date Deposited:

21 Aug 2018 11:31

Last Modified:

18 Jan 2019 14:18

Publisher DOI:

10.1172/JCI94956

PubMed ID:

29408805

Uncontrolled Keywords:

Development Embryonic development Embryonic stem cells Hematology

BORIS DOI:

10.7892/boris.119379

URI:

https://boris.unibe.ch/id/eprint/119379

Actions (login required)

Edit item Edit item
Provide Feedback