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  2. MK2 promotes Tfcp2l1 degradation via β-TrCP ubiquitin ligase to regulate mouse embryonic stem cell self-renewal

MK2 promotes Tfcp2l1 degradation via β-TrCP ubiquitin ligase to regulate mouse embryonic stem cell self-renewal

  • Cell Rep. 2021 Nov 2;37(5):109949. doi: 10.1016/j.celrep.2021.109949.
Yan Zhang 1 Huiwen Ding 1 Xiaoxiao Wang 2 Xin Wang 1 Shengpeng Wan 1 Anchun Xu 1 Ruoyi Gan 1 Shou-Dong Ye 3
Affiliations

Affiliations

  • 1 Center for Stem Cell and Translational Medicine, School of Life Sciences, Anhui University, Hefei, Anhui 230601, China.
  • 2 The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230001, China.
  • 3 Center for Stem Cell and Translational Medicine, School of Life Sciences, Anhui University, Hefei, Anhui 230601, China; Institute of Physical Science and Information Technology, Anhui University, Hefei, Anhui 230601, China. Electronic address: shdye@126.com.
Abstract

Tfcp2l1 can maintain mouse embryonic stem cell (mESC) self-renewal. However, it remains unknown how Tfcp2l1 protein stability is regulated. Here, we demonstrate that β-transducin repeat-containing protein (β-TrCP) targets Tfcp2l1 for ubiquitination and degradation in a mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2)-dependent manner. Specifically, β-TrCP1 and β-TrCP2 recognize and ubiquitylate Tfcp2l1 through the canonical β-TrCP-binding motif DSGDNS, in which the serine residues have been phosphorylated by MK2. Point mutation of serine-to-alanine residues reduces β-TrCP-mediated ubiquitylation and enhances the ability of Tfcp2l1 to promote mESC self-renewal while repressing the speciation of the endoderm, mesoderm, and trophectoderm. Similarly, inhibition of MK2 reduces the association of Tfcp2l1 with β-TrCP1 and increases the self-renewal-promoting effects of Tfcp2l1, whereas overexpression of MK2 or β-TrCP genes decreases Tfcp2l1 protein levels and induces mESC differentiation. Collectively, our study reveals a posttranslational modification of Tfcp2l1 that will expand our understanding of the regulatory network of stem cell pluripotency.

Keywords

MK2; Tfcp2l1; degradation; embryonic stem cells; self-renewal; β-TrCP1.

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