title: AUF-1 and YB-1 independently regulate β-globin mRNA in developing erythroid cells through interactions with poly(A)-binding protein.
abstract: The normal expression of β-globin protein in mature erythrocytes is critically dependent on post-transcriptional events in erythroid progenitors that ensure the high stability of β-globin mRNA. Previous work has revealed that these regulatory processes require AUF-1 and YB-1, two RNA-binding proteins that assemble an mRNP β-complex on the β-globin 3'UTR. Here, we demonstrate that the β-complex organizes during the erythropoietic interval when both β-globin mRNA and protein accumulate rapidly, implicating the importance of this regulatory mRNP to normal erythroid differentiation. Subsequent functional analyses link β-complex assembly to the half-life of β-globin mRNA in vivo, providing a mechanistic basis for this regulatory activity. AUF-1 and YB-1 appear to serve a redundant post-transcriptional function, as both β-complex assembly and β-globin mRNA levels are reduced by coordinate depletion of the two factors, and can be restored by independent rescue with either factor alone. Additional studies demonstrate that the β-complex assembles more efficiently on polyadenylated transcripts, implicating a model in which the β-complex enhances the binding of PABPC1 to the poly(A) tail, inhibiting mRNA deadenylation and consequently effecting the high half-life of β-globin transcripts in erythroid progenitors. These data specify a post-transcriptional mechanism through which AUF1 and YB1 contribute to the normal development of erythropoietic cells, as well as to non-hematopoietic tissues in which AUF1- and YB1-based regulatory mRNPs have been observed to assemble on heterologous mRNAs.
authors.affiliation: Department of Medicine (Hematology-Oncology), Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA.
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: van Zalen
authors.affiliation: Department of Medicine (Hematology-Oncology), Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA.
authors.forename: Alyssa A
authors.initials: AA
authors.lastname: Lombardi
authors.affiliation: Department of Medicine (Hematology-Oncology), Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA.
authors.forename: Grace R
authors.initials: GR
authors.lastname: Jeschke
authors.affiliation: Department of Medicine (Hematology-Oncology), Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA.
authors.forename: Elizabeth O
authors.initials: EO
authors.lastname: Hexner
authors.affiliation: Department of Medicine (Hematology-Oncology), Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA. Electronic address: jeruss@mail.med.upenn.edu.
authors.forename: J Eric
authors.initials: JE
authors.lastname: Russell
mesh_terms: D020413:3' Untranslated Regions; D002454:Cell Differentiation; D002460:Cell Line; D041905:Erythroid Cells / Q000378:metabolism*; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D / Q000378:metabolism*; D006801:Humans; D039103:Poly(A)-Binding Protein II / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051840:Y-Box-Binding Protein 1 / Q000378:metabolism*; D055544:beta-Globins / Q000235:genetics / Q000378:metabolism*
chemical_list: D020413:3' Untranslated Regions; C000630986:HNRNPD protein, human; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; D039103:Poly(A)-Binding Protein II; D012333:RNA, Messenger; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D055544:beta-Globins
keywords: Erythroid development; mRNA stability; β globin