Institute of Translational Medicine, Tianjin Union Medical Center, State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Frontiers Science Center for Cell Responses, National Demonstration Center for Experimental Biology Education and College of Life Sciences, Nankai University, Tianjin 300071, China.
Development. 2022 Jun 15;149(12). doi: 10.1242/dev.200527. Epub 2022 Jun 20.
HBXIP, also named LAMTOR5, has been well characterized as a transcriptional co-activator in various cancers. However, the role of Hbxip in normal development remains unexplored. Here, we demonstrated that homozygous knockout of Hbxip leads to embryonic lethality, with retarded growth around E7.5, and that depletion of Hbxip compromises the self-renewal of embryonic stem cells (ESCs), with reduced expression of pluripotency genes, reduced cell proliferation and decreased colony-forming capacity. In addition, both Hbxip-/- ESCs and E7.5 embryos displayed defects in ectodermal and mesodermal differentiation. Mechanistically, Hbxip interacts with other components of the Ragulator complex, which is required for mTORC1 activation by amino acids. Importantly, ESCs depleted of Ragulator subunits, Lamtor3 or Lamtor4, displayed differentiation defects similar to those of Hbxip-/- ESCs. Moreover, Hbxip-/-, p14-/- and p18-/- mice, lacking subunits of the Ragulator complex, also shared similar phenotypes, embryonic lethality and retarded growth around E7-E8. Thus, we conclude that Hbxip plays a pivotal role in the development and differentiation of the epiblast, as well as the self-renewal and differentiation of ESCs, through activating mTORC1 signaling.
HBXIP，也称为 LAMTOR5，已被很好地描述为各种癌症中的转录共激活因子。然而，Hbxip 在正常发育中的作用仍未被探索。在这里，我们证明 Hbxip 的纯合缺失导致胚胎致死，E7.5 左右生长迟缓，Hbxip 的耗竭使胚胎干细胞（ESCs）的自我更新受损，多能性基因表达减少，细胞增殖减少，集落形成能力降低。此外，Hbxip-/- ESCs 和 E7.5 胚胎都显示出外胚层和中胚层分化缺陷。在机制上，Hbxip 与 Ragulator 复合物的其他成分相互作用，该复合物对于氨基酸激活 mTORC1 是必需的。重要的是，缺失 Ragulator 亚基 Lamtor3 或 Lamtor4 的 ESCs 显示出与 Hbxip-/- ESCs 相似的分化缺陷。此外，缺乏 Ragulator 复合物亚基 Hbxip、p14-/- 和 p18-/- 的小鼠也表现出相似的表型、胚胎致死和 E7-E8 左右生长迟缓。因此，我们得出结论，Hbxip 通过激活 mTORC1 信号通路，在胚胎外胚层的发育和分化以及 ESCs 的自我更新和分化中发挥关键作用。
