Homodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation

Dongmei Wang, Tao Sun, Yuan Xia, Zhe Zhao, Xue Sheng, Shuying Li, Yuechan Ma, Mingying Li, Xiuhua Su, Fan Zhang, Peng Li, Daoxin Ma, Jingjing Ye, Fei Lu () and Chunyan Ji ()
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Dongmei Wang: Qilu Hospital of Shandong University
Tao Sun: Qilu Hospital of Shandong University
Yuan Xia: Qilu Hospital of Shandong University
Zhe Zhao: Qilu Hospital of Shandong University
Xue Sheng: Qilu Hospital of Shandong University
Shuying Li: Qilu Hospital of Shandong University
Yuechan Ma: Qilu Hospital of Shandong University
Mingying Li: Qilu Hospital of Shandong University
Xiuhua Su: Qilu Hospital of Shandong University
Fan Zhang: Qilu Hospital of Shandong University
Peng Li: Qilu Hospital of Shandong University
Daoxin Ma: Qilu Hospital of Shandong University
Jingjing Ye: Qilu Hospital of Shandong University
Fei Lu: Qilu Hospital of Shandong University
Chunyan Ji: Qilu Hospital of Shandong University

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract CCAAT/enhancer binding protein α (C/EBPα) regulates myeloid differentiation, and its dysregulation contributes to acute myeloid leukaemia (AML) progress. Clarifying its functional implementation mechanism is of great significance for its further clinical application. Here, we show that C/EBPα regulates AML cell differentiation through liquid-liquid phase separation (LLPS), which can be disrupted by C/EBPα-p30. Considering that C/EBPα-p30 inhibits the functions of C/EBPα through the LZ region, a small peptide TAT-LZ that could instantaneously interfere with the homodimerization of C/EBPα-p42 was constructed, and dynamic inhibition of C/EBPα phase separation was observed, demonstrating the importance of C/EBPα-p42 homodimers for its LLPS. Mechanistically, homodimerization of C/EBPα-p42 mediated its phosphorylation at the novel phosphorylation site S16, which promoted LLPS and subsequent AML cell differentiation. Finally, decreasing the endogenous C/EBPα-p30/C/EBPα-p42 ratio rescued the phase separation of C/EBPα in AML cells, which provided a new insight for the treatment of the AML.

Date: 2023
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DOI: 10.1038/s41467-023-42650-3

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