The 3' untranslated region of the membrane-bound IL-1R accessory protein mRNA confers tissue-specific destabilization.
IL-1alpha and IL-1beta are proinflammatory cytokines that promote activation of intracellular signaling cascades, leading to stabilization of certain mRNAs and activation of transcription factors. IL-1R type I (IL-1RI) binds IL-1alpha and IL-1beta, and subsequent recruitment of the membrane-bound IL-1R accessory protein (mIL-1RAcP) facilitates signal transduction. Two alternatively spliced isoforms, soluble IL-1RAcP (sIL-1RAcP) and sIL-1RAcP-beta, which lack transmembrane and intracellular domains, have been described. The sIL-1RAcP and possibly sIL-1RAcP-beta can inhibit IL-1 signaling. Proportional expression of the different IL-1RAcP splice variants may be an important determinant of responsiveness to IL-1. We show that although both mIL-1RAcP and sIL-1RAcP mRNAs are widely expressed in human tissue, their relative proportions differ significantly in a tissue-specific manner. Turnover studies revealed that the sIL-1RAcP mRNA has a half-life of approximately 48 h in both the kidney cell line 293 and the hepatoma cell line HepG2. The mIL-1RAcP mRNA has a similar half-life in 293 cells, but a considerably shorter half-life of approximately 5 h in HepG2 cells. Using luciferase reporter constructs, we demonstrated that this specific destabilization of the mIL-1RAcP mRNA in the latter cell type is mediated by its 2.8-kb 3'-untranslated region. Deletion analysis further established that the cell line-specific instability does not involve AU-rich elements, but is mediated by several novel elements that appear to act independently; such elements may be recognized by proteins expressed specifically in some, but not all, tissues. These data demonstrate that the cellular capacity to respond to IL-1 is tightly regulated in a tissue-specific manner.
Jensen
Liselotte E
LE
Department of Pharmacology and Center for Pharmacogenetics, University of Pennsylvania School of Medicine, 156 Johnson Pavilion, 3620 Hamilton Walk, Philadelphia, PA 19104, USA. jensen@pharm.med.upenn.edu
Whitehead
Alexander S
AS
D020413:3' Untranslated Regions / Q000378:metabolism / Q000502:physiology*; D017398:Alternative Splicing; D001483:Base Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015252:Deoxyribonucleases, Type II Site-Specific / Q000235:genetics; D005786:Gene Expression Regulation / Q000276:immunology; D005822:Genetic Vectors; D006207:Half-Life; D006801:Humans; D053577:Interleukin-1 Receptor Accessory Protein; D008969:Molecular Sequence Data; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D011506:Proteins / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D020871:RNA Stability / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000502:physiology*; D012045:Regulatory Sequences, Nucleic Acid / Q000502:physiology*; D012995:Solubility
D020413:3' Untranslated Regions; C507765:IL1RAP protein, human; D053577:Interleukin-1 Receptor Accessory Protein; D020033:Protein Isoforms; D011506:Proteins; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; C074326:CTTAAG-specific type II deoxyribonucleases; D015252:Deoxyribonucleases, Type II Site-Specific; C060616:TGGCCA-specific type II deoxyribonucleases