P38α/JNK signaling restrains erythropoiesis by suppressing Ezh2-mediated epigenetic silencing of Bim

Ping Hu, Angel R. Nebreda, Helmut Hanenberg, Garrett H. Kinnebrew, Mircea Ivan, Mervin C. Yoder, Marie-Dominique Filippi, Hal E. Broxmeyer and Reuben Kapur ()
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Ping Hu: Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis
Angel R. Nebreda: Institute for Research in Biomedicine (IRB Barcelona). Barcelona Institute of Science and Technology
Helmut Hanenberg: University Children’s Hospital Essen, University of Duisburg-Essen
Garrett H. Kinnebrew: Indiana University School of Medicine, Indianapolis
Mircea Ivan: Indiana University School of Medicine, Indianapolis
Mervin C. Yoder: Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis
Marie-Dominique Filippi: Cincinnati Children’s Research Foundation, University of Cincinnati College of Medicine
Hal E. Broxmeyer: Indiana University School of Medicine
Reuben Kapur: Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract While erythropoietin (EPO) constitutes the major treatment for anemia, a range of anemic disorders remain resistant to EPO treatment. The need for alternative therapeutic strategies requires the identification of mechanisms that physiologically restrain erythropoiesis. Here we show that P38α restrains erythropoiesis in mouse and human erythroblasts independently of EPO by integrating apoptotic signals during recovery from anemia. P38α deficiency promotes JNK activation through increased expression of Map3k4 via a negative feedback mechanism. JNK prevents Cdk1-mediated phosphorylation and subsequent degradation by Smurf2 of the epigenetic silencer Ezh2. Stabilized Ezh2 silences Bim expression and protects erythroblasts from apoptosis. Thus, we identify P38α/JNK signaling as a molecular brake modulating erythropoiesis through epigenetic silencing of Bim. We propose that inhibition of P38α, by enhancing erythropoiesis in an EPO-independent fashion, may provide an alternative strategy for the treatment of anemia.

Date: 2018
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DOI: 10.1038/s41467-018-05955-2

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