miR-451 protects against erythroid oxidant stress by repressing 14-3-3zeta.
The bicistronic microRNA (miRNA) locus miR-144/451 is highly expressed during erythrocyte development, although its physiological roles are poorly understood. We show that miR-144/451 ablation in mice causes mild erythrocyte instability and increased susceptibility to damage after exposure to oxidant drugs. This phenotype is deeply conserved, as miR-451 depletion synergizes with oxidant stress to cause profound anemia in zebrafish embryos. At least some protective activities of miR-451 stem from its ability to directly suppress production of 14-3-3zeta, a phospho-serine/threonine-binding protein that inhibits nuclear accumulation of transcription factor FoxO3, a positive regulator of erythroid anti-oxidant genes. Thus, in miR-144/451(-/-) erythroblasts, 14-3-3zeta accumulates, causing partial relocalization of FoxO3 from nucleus to cytoplasm with dampening of its transcriptional program, including anti-oxidant-encoding genes Cat and Gpx1. Supporting this mechanism, overexpression of 14-3-3zeta in erythroid cells and fibroblasts inhibits nuclear localization and activity of FoxO3. Moreover, shRNA suppression of 14-3-3zeta protects miR-144/451(-/-) erythrocytes against peroxide-induced destruction, and restores catalase activity. Our findings define a novel miRNA-regulated pathway that protects erythrocytes against oxidant stress, and, more generally, illustrate how a miRNA can influence gene expression by altering the activity of a key transcription factor.
Yu
Duonan
D
Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
dos Santos
Camila O
CO
Zhao
Guowei
G
Jiang
Jing
J
Amigo
Julio D
JD
Khandros
Eugene
E
Dore
Louis C
LC
Yao
Yu
Y
D'Souza
Janine
J
Zhang
Zhe
Z
Ghaffari
Saghi
S
Choi
John
J
Friend
Sherree
S
Tong
Wei
W
Orange
Jordan S
JS
Paw
Barry H
BH
Weiss
Mitchell J
MJ
D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus; D000818:Animals; D001483:Base Sequence; D002374:Catalase / Q000378:metabolism; D041905:Erythroid Cells / Q000201:enzymology / Q000378:metabolism*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D016415:Sequence Alignment; D017384:Sequence Deletion / Q000235:genetics; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism
D048948:14-3-3 Proteins; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C551064:MIRN144 microRNA, mouse; D035683:MicroRNAs; C550758:Mirn451 microRNA, mouse; D002374:Catalase