Year: 2008
Type: article
Abstract: Hemoglobin production during erythropoiesis is mechanistically coupled to the acquisition and metabolism of iron. We discovered that iron regulates the expression of alpha-hemoglobin-stabilizing protein (AHSP), a molecular chaperone that binds and stabilizes free alpha-globin during hemoglobin synthesis. In primates, the 3'-untranslated region (UTR) of AHSP mRNA contains a nucleotide sequence resembling iron responsive elements (IREs), stem-loop structures that regulate gene expression post-transcriptionally by binding iron regulatory proteins (IRPs). The AHSP IRE-like stem-loop deviates from classical consensus sequences and binds IRPs poorly in electrophoretic mobility shift assays. However, in cytoplasmic extracts, AHSP mRNA co-immunoprecipitates with IRPs in a fashion that is dependent on the stem-loop structure and inhibited by iron. Moreover, this interaction enhances AHSP mRNA stability in erythroid and heterologous cells. Our findings demonstrate that IRPs can regulate mRNA expression through non-canonical IREs and extend the repertoire of known iron-regulated genes. In addition, we illustrate a new mechanism through which hemoglobin may be modulated according to iron status.
Source: Journal of Biological Chemistry
Institutions: Children's Hospital of Philadelphia, University of Pennsylvania, Pennsylvania State University, National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Wake Forest University Health Sciences, Wake Forest University, University of Wisconsin–Madison, Universidade Estadual de Campinas (UNICAMP)
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
Awards: G3309888733, Global Predictions and Tests of Erythroid Regulation, G459174223, Hereditary hemoglobin disorders: molecular genetics, clinical features and animal models with the production of transgenic animals, Biological Functions of Iron Responsive Elements, The Role of Alpha Hemoglobin Stabilizing Protein in Human Beta Thalassemia, Trim58 and the Ubiquitin Proteasome System in Erythro-megakaryopoiesis, G7870658753, G9000050649, G9000051814, G9000123879, G9000307971
OpenAlex ID: W2033098256