RNA-binding proteins heterogeneous nuclear ribonucleoprotein A1, E1, and K are involved in post-transcriptional control of collagen I and III synthesis.
Collagen types I and III, coded by COL1A1/COL1A2 and COL3A1 genes, are the major fibrillar collagens produced by fibroblasts, including cardiac fibroblasts of the adult heart. Characteristic for different cardiomyopathies is a remodeling process associated with an upregulation of collagen synthesis, which leads to fibrosis. We report identification of three mRNA-binding proteins, heterogeneous nuclear ribonucleoprote (hnRNP) A1, E1, and K, as positive effectors of collagen synthesis acting at the post-transcriptional level by interaction with the 3'-untranslated regions (3'-UTRs) of COL1A1, 1A2, and 3A1 mRNAs. In vitro, binding experiments (electromobility shift assay and UV cross-linking) reveal significant differences in binding to CU- and AU-rich binding motifs. Reporter gene cell transfection experiments and RNA stability assays show that hnRNPs A1, E1, and K stimulate collagen expression by stabilizing mRNAs. Collagen synthesis is activated via the angiotensin II type 1 (AT1) receptor. We demonstrate that transforming growth factor-beta1, a major product of stimulated AT1 receptor, does not activate solely collagen synthesis but synergistically the synthesis of hnRNP A1, E1, and K as well. Thus, post-transcriptional control of collagen synthesis at the mRNA level may substantially be caused by alteration of the expression of RNA-binding proteins. The pathophysiological impact of this finding was demonstrated by screening the expression of hnRNP E1 and K in cardiovascular diseases. In the heart muscle of patients experiencing aortic stenosis, ischemic cardiomyopathy, or dilatative cardiomyopathy, a significant increase in the expression of hnRNP E1, A1, and K was found between 1.5- and 4.5-fold relative to controls.
Thiele
Bernd-Joachim
BJ
Institut für Physiologie, University-Medicine Berlin, Germany.
Doller
Anke
A
Kähne
Thilo
T
Pregla
Reinhard
R
Hetzer
Roland
R
Regitz-Zagrosek
Vera
V
D020413:3' Untranslated Regions / Q000378:metabolism*; D001024:Aortic Valve Stenosis / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics*; D024042:Collagen Type I / Q000096:biosynthesis / Q000235:genetics*; D000090602:Collagen Type I, alpha 1 Chain; D024061:Collagen Type III / Q000096:biosynthesis / Q000235:genetics*; D004268:DNA-Binding Proteins; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D012333:RNA, Messenger / Q000096:biosynthesis; D016601:RNA-Binding Proteins; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012261:Ribonucleoproteins / Q000378:metabolism / Q000502:physiology*; D013951:Thymus Hormones / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000502:physiology; D053773:Transforming Growth Factor beta1
D020413:3' Untranslated Regions; C439971:COL3A1 protein, human; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D024061:Collagen Type III; D004268:DNA-Binding Proteins; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D034441:Heterogeneous-Nuclear Ribonucleoproteins; C094604:PCBP1 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D044140:Receptor, Angiotensin, Type 1; D011993:Recombinant Fusion Proteins; D012261:Ribonucleoproteins; C508960:TGFB1 protein, human; D013951:Thymus Hormones; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C000619656:hnRNPA1 protein, human; C072074:HNRNPK protein, human; D003094:Collagen