Shanghai Institute of Hematology, CNRS-LIA Hematology and Cancer, Sino-French Research Center for Life Sciences and Genomics, State Key Laboratory of Medical Genomics, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
Department of hematology, Shanghai General Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
PLoS Genet. 2021 Aug 5;17(8):e1009693. doi: 10.1371/journal.pgen.1009693. eCollection 2021 Aug.
The ubiquitin-proteasome system plays important roles in various biological processes as it degrades the majority of cellular proteins. Adequate proteasomal degradation of crucial transcription regulators ensures the proper development of neutrophils. The ubiquitin E3 ligase of Growth factor independent 1 (GFI1), a key transcription repressor governing terminal granulopoiesis, remains obscure. Here we report that the deficiency of the ring finger protein Interferon regulatory factor 2 binding protein 2a (Irf2bp2a) leads to an impairment of neutrophils differentiation in zebrafish. Mechanistically, Irf2bp2a functions as a ubiquitin E3 ligase targeting Gfi1aa for proteasomal degradation. Moreover, irf2bp2a gene is repressed by Gfi1aa, thus forming a negative feedback loop between Irf2bp2a and Gfi1aa during neutrophils maturation. Different levels of GFI1 may turn it into a tumor suppressor or an oncogene in malignant myelopoiesis. Therefore, discovery of certain drug targets GFI1 for proteasomal degradation by IRF2BP2 might be an effective anti-cancer strategy.
泛素-蛋白酶体系统在各种生物过程中发挥着重要作用，因为它可以降解大多数细胞蛋白质。适当的蛋白酶体降解关键转录调节剂可确保中性粒细胞的正常发育。生长因子独立 1（GFI1）的泛素 E3 连接酶，是控制终末粒细胞生成的关键转录抑制剂，其作用仍不清楚。在这里，我们报告干扰素调节因子 2 结合蛋白 2a（Irf2bp2a）的缺失导致斑马鱼中性粒细胞分化受损。从机制上讲，Irf2bp2a 作为一种泛素 E3 连接酶，可靶向 Gfi1aa 进行蛋白酶体降解。此外，irf2bp2a 基因受到 Gfi1aa 的抑制，因此在中性粒细胞成熟过程中，Irf2bp2a 和 Gfi1aa 之间形成负反馈回路。GFI1 的不同水平可能使其在恶性髓系细胞生成中成为抑癌基因或癌基因。因此，发现某些药物靶点 GFI1 通过 IRF2BP2 进行蛋白酶体降解可能是一种有效的抗癌策略。
