Yu, Duonan, dos Santos, Camila O, Zhao, Guowei, Jiang, Jing, Amigo, Julio D, Khandros, Eugene, Dore, Louis C, Yao, Yu, D'Souza, Janine, Zhang, Zhe, Ghaffari, Saghi, Choi, John, Friend, Sherree, Tong, Wei, Orange, Jordan S, Paw, Barry H, Weiss, Mitchell J (August 2010) miR-451 protects against erythroid oxidant stress by repressing 14-3-3zeta. Genes and Development, 24 (15). pp. 1620-1633. ISSN 0890-9369
Abstract
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.
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