Identification of TWSG1 as a second novel erythroid regulator of hepcidin expression in murine and human cells.
In thalassemia and other iron loading anemias, ineffective erythropoiesis and erythroid signaling molecules are thought to cause inappropriate suppression of a small peptide produced by hepatocytes named hepcidin. Previously, it was reported that the erythrokine GDF15 is expressed at very high levels in thalassemia and suppresses hepcidin expression. In this study, erythroblast expression of a second molecule named twisted gastrulation (TWSG1) was explored as a potential erythroid regulator of hepcidin. Transcriptome analyses suggest TWSG1 is produced during the earlier stages of erythropoiesis. Hepcidin suppression assays demonstrated inhibition by TWSG1 as measured by quantitative polymerase chain reaction (PCR) in dosed assays (1-1000 ng/mL TWSG1). In human cells, TWSG1 suppressed hepcidin indirectly by inhibiting the signaling effects and associated hepcidin up-regulation by bone morphogenic proteins 2 and 4 (BMP2/BMP4). In murine hepatocytes, hepcidin expression was inhibited by murine Twsg1 in the absence of additional BMP. In vivo studies of Twsg1 expression were performed in healthy and thalassemic mice. Twsg1 expression was significantly increased in the spleen, bone marrow, and liver of the thalassemic animals. These data demonstrate that twisted gastrulation protein interferes with BMP-mediated hepcidin expression and may act with GDF15 to dysregulate iron homeostasis in thalassemia syndromes.
Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Toshihiko
T
Tanno
Prashanth
P
Porayette
Orapan
O
Sripichai
Seung-Jae
SJ
Noh
Colleen
C
Byrnes
Ajoy
A
Bhupatiraju
Y Terry
YT
Lee
Julia B
JB
Goodnough
Omid
O
Harandi
Tomas
T
Ganz
Robert F
RF
Paulson
Jeffery L
JL
Miller
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000502:physiology*; D055396:Bone Morphogenetic Protein 2 / Q000502:physiology; D055415:Bone Morphogenetic Protein 4 / Q000502:physiology; D016207:Cytokines / Q000235:genetics / Q000502:physiology*; D004920:Erythropoiesis / Q000235:genetics / Q000502:physiology*; D005260:Female; D055436:Growth Differentiation Factor 15 / Q000235:genetics / Q000502:physiology; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D064451:Hepcidins; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D051785:Smad Proteins / Q000502:physiology; D013789:Thalassemia / Q000097:blood / Q000235:genetics / Q000473:pathology / Q000503:physiopathology
D023181:Antimicrobial Cationic Peptides; C525719:Bmp2 protein, mouse; C525810:Bmp4 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D016207:Cytokines; C526140:GDF15 protein, human; C526141:Gdf15 protein, mouse; D055436:Growth Differentiation Factor 15; C578702:HAMP protein, human; C579599:Hamp protein, mouse; D064451:Hepcidins; D011506:Proteins; D051785:Smad Proteins; C576635:TWSG1 protein, human; C473561:twisted gastrulation protein, mouse; D007501:Iron