Regulation of eIF4E guides a unique translational program to control erythroid maturation

Author:

Forester Craig M.1234ORCID,Oses-Prieto Juan A.5ORCID,Phillips Nancy J.5,Miglani Sohit3456ORCID,Pang Xiaming345,Byeon Gun Woo7ORCID,DeMarco Rachel1,Burlingame Al5ORCID,Barna Maria7ORCID,Ruggero Davide345ORCID

Affiliation:

1. Department of Pediatrics, University of Colorado, Denver, CO 80045, USA.

2. Division of Pediatric Hematology/Oncology/Bone Marrow Transplant, Children’s Hospital Colorado, University of Colorado-Anschutz Medical Campus, Aurora, CO 80045, USA.

3. Department of Urology, University of California, San Francisco, San Francisco, CA, USA.

4. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, CA 94158, USA.

5. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.

6. Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.

7. Department of Genetics, Stanford University School of Medicine, Stanford, CA 94309, USA.

Abstract

Translation control is essential in balancing hematopoietic precursors and differentiation; however, the mechanisms underlying this program are poorly understood. We found that the activity of the major cap-binding protein eIF4E is unexpectedly regulated in a dynamic manner throughout erythropoiesis that is uncoupled from global protein synthesis rates. Moreover, eIF4E activity directs erythroid maturation, and increased eIF4E expression maintains cells in an early erythroid state associated with a translation program driving the expression of PTPN6 and Igf2bp1. A cytosine-enriched motif in the 5′ untranslated region is important for eIF4E-mediated translation specificity. Therefore, selective translation of key target genes necessary for the maintenance of early erythroid states by eIF4E highlights a unique mechanism used by hematopoietic precursors to rapidly elicit erythropoietic maturation upon need.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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