A temporal difference in the stabilization of two mRNAs with a 3' iron-responsive element during iron deficiency

The interactions of iron regulatory proteins (IRPs) with mRNAs containing an iron-responsive element (IRE) maintain cellular iron homeostasis and coordinate it with metabolism and possibly cellular behavior. The mRNA encoding transferrin receptor-1 ( , TfR1), which is a major means of iron importati...

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Bibliographic Details
Published in:RNA (Cambridge) 2023-08, Vol.29 (8), p.1117-1125
Main Authors: Connell, Gregory J, Abasiri, Ikedinachukwu Michael, Chaney, Elizabeth H
Format: Article
Language:English
Subjects:
3' Untranslated Regions
Alternative splicing
Cell division
HEK293 Cells
Homeostasis
Humans
Iron
Iron - metabolism
Iron Deficiencies
Iron deficiency
mRNA stability
mRNA turnover
Nutrient deficiency
Receptors, Transferrin - genetics
Receptors, Transferrin - metabolism
Regulatory proteins
Regulatory sequences
RNA, Messenger - genetics
RNA, Messenger - metabolism
Uridine
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Summary:The interactions of iron regulatory proteins (IRPs) with mRNAs containing an iron-responsive element (IRE) maintain cellular iron homeostasis and coordinate it with metabolism and possibly cellular behavior. The mRNA encoding transferrin receptor-1 ( , TfR1), which is a major means of iron importation, has five IREs within its 3' UTR, and IRP interactions help maintain cytosolic iron through the protection of the TfR1 mRNA from degradation. An IRE within the 3' UTR of an mRNA splice variant encoding human cell division cycle 14A ( ) has the potential to coordinate the cellular iron status with cellular behavior through a similar IRP-mediated mechanism. However, the stability of the splice variant was reported earlier to be unaffected by the cellular iron status, which suggested that the IRE is not functional. We labeled newly synthesized mRNA in HEK293 cells with 5-ethynyl uridine and found that the stability of the variant is responsive to iron deprivation, but there are two major differences from the regulation of TfR1 mRNA stability. First, the decay of the mRNA does not utilize the Roquin-mediated reaction that acts on the TfR1 mRNA, indicating that there is flexibility in the degradative machinery antagonized by the IRE-IRP interactions. Second, the stabilization of the mRNA is delayed relative to the TfR1 mRNA and does not occur until IRP binding activity has been induced. The result is consistent with a hierarchy of IRP interactions in which the maintenance of cellular iron through the stabilization of the TfR1 mRNA is initially prioritized.
ISSN:1355-8382
1469-9001
1469-9001
DOI:10.1261/rna.079665.123