An iron responsive element-like stem-loop regulates alpha-hemoglobin-stabilizing protein mRNA.
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.
dos Santos
Camila O
CO
Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
Dore
Louis C
LC
Valentine
Eric
E
Shelat
Suresh G
SG
Hardison
Ross C
RC
Ghosh
Manik
M
Wang
Wei
W
Eisenstein
Richard S
RS
Costa
Fernando F
FF
Weiss
Mitchell J
MJ
D020413:3' Untranslated Regions / Q000235:genetics / Q000378:metabolism*; D001798:Blood Proteins / Q000235:genetics / Q000378:metabolism*; D004920:Erythropoiesis / Q000502:physiology*; D006367:HeLa Cells; D006454:Hemoglobins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007501:Iron / Q000378:metabolism*; D020014:K562 Cells; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009690:Nucleic Acid Conformation; D020871:RNA Stability / Q000502:physiology*
D020413:3' Untranslated Regions; C468768:AHSP protein, human; D001798:Blood Proteins; D006454:Hemoglobins; D018832:Molecular Chaperones; D007501:Iron