Dynamic Regulation of a Ribosome Rescue Pathway in Erythroid Cells and Platelets

• Published in: Cell reports (Cambridge) 2016-09, Vol.17 (1), p.1-10
• Main Authors: Mills, Eric W., Wangen, Jamie, Green, Rachel, Ingolia, Nicholas T.
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions; ATP-Binding Cassette Transporters - deficiency; ATP-Binding Cassette Transporters - genetics; Blood Platelets - cytology; Blood Platelets - metabolism; Cell Differentiation; Cell Line, Tumor; Dom34; Endonucleases; erythropoiesis; GTP-Binding Proteins - genetics; GTP-Binding Proteins - metabolism; Hemoglobins - biosynthesis; Hemoglobins - genetics; HSP70 Heat-Shock Proteins - genetics; HSP70 Heat-Shock Proteins - metabolism; Humans; K562 Cells; Megakaryocyte Progenitor Cells - cytology; Megakaryocyte Progenitor Cells - metabolism; Microfilament Proteins - genetics; Microfilament Proteins - metabolism; Nuclear Proteins; Pelota; Peptide Elongation Factors - genetics; Peptide Elongation Factors - metabolism; Primary Cell Culture; Protein Biosynthesis; reticulocyte; Reticulocytes - cytology; Reticulocytes - metabolism; ribosome recycling; ribosome rescue; Ribosomes - chemistry; Ribosomes - metabolism; thrombopoiesis
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.08.088

Protein synthesis continues in platelets and maturing reticulocytes, although these blood cells lack nuclei and do not make new mRNA or ribosomes. Here, we analyze translation in primary human cells from anucleate lineages by ribosome profiling and uncover a dramatic accumulation of post-termination unrecycled ribosomes in the 3′ UTRs of mRNAs. We demonstrate that these ribosomes accumulate as a result of the natural loss of the ribosome recycling factor ABCE1 during terminal differentiation. Induction of the ribosome rescue factors PELO and HBS1L is required to support protein synthesis when ABCE1 levels fall and for hemoglobin production during blood cell development. Our observations suggest that this distinctive loss of ABCE1 in anucleate blood lineages could sensitize them to defects in ribosome homeostasis, perhaps explaining in part why genetic defects in the fundamental process of ribosome production (“ribosomopathies”) often affect hematopoiesis specifically. [Display omitted] •Primary reticulocyte and platelet ribosome profiling reveals 3′ UTR ribosome buildup•Decreased ABCE1 during differentiation leads to ribosome recycling failure•Regulation of the ribosome rescue factors PELO/HBS1L compensates for recycling defects Maturing mammalian platelets and red blood cells lack nuclei but continue protein synthesis during terminal differentiation. Using ribosome profiling, Mills et al. report abundant 3′ UTR ribosomes in these lineages and show how interplay between the ribosome rescue/recycling factors PELO and ABCE1 may promote translation of critical mRNAs during differentiation.