Institut de recherches cliniques de Montréal-IRCM, Montréal, QC, Canada.
Institut de recherches cliniques de Montréal-IRCM, Montréal, QC, Canada; Département de microbiologie, infectiologie et immunologie, Université de Montréal, Montréal, QC, Canada; Division of Experimental Medicine, McGill University, Montréal, QC, Canada.
Adv Immunol. 2021;149:35-94. doi: 10.1016/bs.ai.2021.03.003. Epub 2021 Apr 23.
GFI1 and GFI1B are small nuclear proteins of 45 and 37kDa, respectively, that have a simple two-domain structure: The first consists of a group of six c-terminal CH zinc finger motifs that are almost identical in sequence and bind to very similar, specific DNA sites. The second is an N-terminal 20 amino acid SNAG domain that can bind to the pocket of the histone demethylase KDM1A (LSD1) near its active site. When bound to DNA, both proteins act as bridging factors that bring LSD1 and associated proteins into the vicinity of methylated substrates, in particular histone H3 or TP53. GFI1 can also bring methyl transferases such as PRMT1 together with its substrates that include the DNA repair proteins MRE11 and 53BP1, thereby enabling their methylation and activation. While GFI1B is expressed almost exclusively in the erythroid and megakaryocytic lineage, GFI1 has clear biological roles in the development and differentiation of lymphoid and myeloid immune cells. GFI1 is required for lymphoid/myeloid and monocyte/granulocyte lineage decision as well as the correct nuclear interpretation of a number of important immune-signaling pathways that are initiated by NOTCH1, interleukins such as IL2, IL4, IL5 or IL7, by the pre TCR or -BCR receptors during early lymphoid differentiation or by T and B cell receptors during activation of lymphoid cells. Myeloid cells also depend on GFI1 at both stages of early differentiation as well as later stages in the process of activation of macrophages through Toll-like receptors in response to pathogen-associated molecular patterns. The knowledge gathered on these factors over the last decades puts GFI1 and GFI1B at the center of many biological processes that are critical for both the innate and acquired immune system.
GFI1 和 GFI1B 分别是 45kDa 和 37kDa 的小核蛋白，具有简单的两结构域结构：第一结构域由六个 C 末端 CH 锌指基序组成，其序列几乎完全相同，与非常相似的特异性 DNA 位点结合。第二结构域是一个 N 末端 20 个氨基酸的 SNAG 结构域，可与组蛋白去甲基酶 KDM1A（LSD1）的活性位点附近的口袋结合。当与 DNA 结合时，这两种蛋白质都充当桥接因子，将 LSD1 和相关蛋白带到甲基化底物的附近，特别是组蛋白 H3 或 TP53。GFI1 还可以将甲基转移酶（如 PRMT1）与其底物结合，包括 DNA 修复蛋白 MRE11 和 53BP1，从而使它们甲基化和激活。虽然 GFI1B 几乎仅在红细胞和巨核细胞谱系中表达，但 GFI1 在淋巴样和髓样免疫细胞的发育和分化中具有明确的生物学作用。GFI1 是淋巴样/髓样和单核细胞/粒细胞谱系决定所必需的，也是由 NOTCH1、白细胞介素（如 IL2、IL4、IL5 或 IL7）、早期淋巴样分化期间的 preTCR 或 -BCR 受体或淋巴细胞激活期间的 T 和 B 细胞受体启动的许多重要免疫信号通路的正确核解释所必需的。髓样细胞在早期分化的两个阶段以及在对病原体相关分子模式作出反应的 Toll 样受体激活巨噬细胞的后期阶段也依赖于 GFI1。过去几十年积累的关于这些因子的知识将 GFI1 和 GFI1B 置于许多对先天和获得性免疫系统都至关重要的生物学过程的中心。
