Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; CNRS-LIA Hematology and Cancer, Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
CNRS-LIA Hematology and Cancer, Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Université de Paris 7/INSERM/CNRS UMR 944/7212, Equipe Labellisée No. 11 Ligue Nationale Contre le Cancer, Hôpital St. Louis, Paris, Cedex 10, France.
Biochim Biophys Acta Gen Subj. 2022 Oct;1866(10):130186. doi: 10.1016/j.bbagen.2022.130186. Epub 2022 Jun 7.
Zebrafish irf2bp2a, an ortholog of human IRF2BP2, is specifically expressed in the developing liver at growth stage. As a multi-functional protein, the role of irf2bp2a during hepatogenesis remains unclear. Here we take advantage of an irf2bp2a knockout line to show that the deficiency of irf2bp2a can induce apoptosis of hepatic cells through aberrant p53 activation at the early stage of embryonic development. Mechanistic studies reveal that within the IRF2BP2-null hepatic cells, more MDM2 molecules, the E3 ubiquitin ligase of P53, can be sequestrated into the IRF2-MDM2 complex, which in turns stabilizes P53 protein. Moreover, irf2bp2a is demonstrated as a direct downstream target of c/ebpα. Thus, a C/ebpα-Irf2bp2a-P53 axis controls liver development in zebrafish. Overall, our findings indicate a stage-specific role of irf2bp2a on liver organogenesis by regulating p53 pathway.
斑马鱼 irf2bp2a 是人类 IRF2BP2 的同源物，在生长阶段特异性表达于发育中的肝脏。作为一种多功能蛋白，irf2bp2a 在肝发生过程中的作用尚不清楚。在这里，我们利用 irf2bp2a 敲除系，通过胚胎发育早期 p53 激活的异常显示 irf2bp2a 的缺乏可诱导肝细胞凋亡。机制研究表明，在 IRF2BP2 缺失的肝细胞中，更多的 MDM2 分子，即 P53 的 E3 泛素连接酶，可以被隔离到 IRF2-MDM2 复合物中，这反过来又稳定了 P53 蛋白。此外，irf2bp2a 被证明是 c/ebpα 的直接下游靶标。因此，C/ebpα-Irf2bp2a-P53 轴控制斑马鱼肝脏的发育。总的来说，我们的研究结果表明 irf2bp2a 通过调节 p53 途径在肝脏器官发生中具有特定阶段的作用。
