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

Nature Communications
Ping HuReuben Kapur

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.

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Citations

Jan 13, 2021·Journal of Enzyme Inhibition and Medicinal Chemistry·Dhanoop Manikoth AyyathanMichael Blank
Dec 15, 2020·Cell & Bioscience·Zhongwei LiJin Bai
Jan 29, 2021·Nature Reviews. Molecular Cell Biology·Begoña Canovas, Angel R Nebreda
Jan 23, 2021·International Journal of Molecular Sciences·Francesca AglialoroEmile van den Akker
Feb 9, 2021·The American Journal of Pathology·Talha AnwarCelina G Kleer
Nov 14, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Haoyang ZhouMark W Feinberg
Jun 26, 2021·Pharmacology & Therapeutics·Tomasz M GrzywaJakub Golab

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Datasets Mentioned

BETA
GM-CSF

Methods Mentioned

BETA
flow cytometry
ELISA
immunoprecipitation
flow
co-immunoprecipitation
ubiquitination
PCR
Transfection
Protein Assay

Software Mentioned

Flowjo
GSEA

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