Methylation of dual-specificity phosphatase 4 controls cell differentiation

Hairui Su, Ming Jiang, Chamara Senevirathne, Srinivas Aluri, Tuo Zhang, Han Guo, Juliana Xavier-Ferrucio, Shuiling Jin, Ngoc Tung Tran, Szu Mam Liu, Chiao Wang Sun, Yongxia Zhu, Qing Zhao, Yuling Chen, Lou Ann Cable, Yudao Shen, Jing Liu, Cheng Kui Qu, Xiaosi Han, Christopher A. KlugRavi Bhatia, Yabing Chen, Stephen D. Nimer, Y. George Zheng, Camelia Iancu-Rubin, Jian Jin, Haiteng Deng, Diane S. Krause, Jenny Xiang, Amit K. Verma, Minkui Luo, Xinyang Zhao

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Mitogen-activated protein kinases (MAPKs) are inactivated by dual-specificity phosphatases (DUSPs), the activities of which are tightly regulated during cell differentiation. Using knockdown screening and single-cell transcriptional analysis, we demonstrate that DUSP4 is the phosphatase that specifically inactivates p38 kinase to promote megakaryocyte (Mk) differentiation. Mechanistically, PRMT1-mediated methylation of DUSP4 triggers its ubiquitinylation by an E3 ligase HUWE1. Interestingly, the mechanistic axis of the DUSP4 degradation and p38 activation is also associated with a transcriptional signature of immune activation in Mk cells. In the context of thrombocytopenia observed in myelodysplastic syndrome (MDS), we demonstrate that high levels of p38 MAPK and PRMT1 are associated with low platelet counts and adverse prognosis, while pharmacological inhibition of p38 MAPK or PRMT1 stimulates megakaryopoiesis. These findings provide mechanistic insights into the role of the PRMT1-DUSP4-p38 axis on Mk differentiation and present a strategy for treatment of thrombocytopenia associated with MDS.

Original languageEnglish (US)
Article number109421
JournalCell Reports
Volume36
Issue number4
DOIs
StatePublished - Jul 27 2021

Keywords

  • DUSP4
  • HUWE1
  • leukemia
  • MDS
  • megakaryocyte
  • myelodysplasia syndrome
  • p38
  • platlet
  • PRMT1
  • trombocytopenia

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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