Separate cis-trans pathways post-transcriptionally regulate murine CD154 (CD40 ligand) expression: a novel function for CA repeats in the 3'-untranslated region.
We report a role for CA repeats in the 3'-untranslated region (3'-UTR) in regulating CD154 expression. Human CD154 is encoded by an unstable mRNA; this instability is conferred in cis by a portion of its 3'-UTR that includes a polypyrimidine-rich region and CA dinucleotide repeat. We demonstrate similar instability activity with the murine CD154 3'-UTR. This instability element mapped solely to a conserved 100-base CU-rich region alone, which we call a CU-rich response element. Surprisingly, the CA dinucleotide-rich region also regulated reporter expression but at the level of translation. This activity was associated with poly(A) tail shortening and regulated by heterogeneous nuclear ribonucleoprotein L levels. We conclude that the CD154 3'-UTR contains dual cis-acting elements, one of which defines a novel function for exonic CA dinucleotide repeats. These findings suggest a mechanism for the association of 3'-UTR CA-rich response element polymorphisms with CD154 overexpression and the subsequent risk of autoimmune disease.
Hamilton
B JoNell
BJ
Department of Medicine, Lebanon, New Hampshire 03756.
Wang
Xiao-Wei
XW
Department of Medicine, Lebanon, New Hampshire 03756.
Collins
Jane
J
Department of Medicine, Lebanon, New Hampshire 03756.
Bloch
Donald
D
Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114.
Bergeron
Alan
A
Department of Microbiology and Immunology, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 03756.
Henry
Brian
B
Department of Medicine, Lebanon, New Hampshire 03756.
Terry
Benjamin M
BM
New York Medical College, Valhalla, New York 10595.
Zan
Moe
M
Department of Medicine, Lebanon, New Hampshire 03756.
Mouland
Andrew J
AJ
Lady Davis Institute for Medical Research and McGill University, Montreal, Quebec H3T 1E2, Canada.
Rigby
William F C
WFC
Department of Medicine, Lebanon, New Hampshire 03756; Department of Microbiology and Immunology, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 03756. Electronic address: William.Rigby@Dartmouth.edu.
D020413:3' Untranslated Regions; D000818:Animals; D001327:Autoimmune Diseases; D001483:Base Sequence; D023201:CD40 Ligand / Q000235:genetics*; D002417:Cattle; D005786:Gene Expression Regulation; D034664:Heterogeneous-Nuclear Ribonucleoprotein L / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D011061:Poly A / Q000378:metabolism; D011110:Polymorphism, Genetic; D012323:RNA Processing, Post-Transcriptional; D012091:Repetitive Sequences, Nucleic Acid
D020413:3' Untranslated Regions; D034664:Heterogeneous-Nuclear Ribonucleoprotein L; D023201:CD40 Ligand; D011061:Poly A