Regulation of B cell development by ABCB7

ABCB7 对 B 细胞发育的调节

• 批准号: 10374116
• 负责人: Virginia Smith Shapiro
• 金额: $ 19.88万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-17 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10374116
• 关键词: B-Cell Development; B-Lymphocytes; Binding; CD19 gene; Cell Count; Cell Death; Cell Maturation; Cell physiology; Cells; Chromatin; Common Lymphoid Progenitor; Cytoplasm; Defect; Development; Dioxygenases; Down-Regulation; Enzymes; Exhibits; Failure; Family; Ferritin; Generations; Genes; Genetic Transcription; Glutathione; Hematopoiesis; Hematopoietic; Heme; Histones; Homeostasis; Immunoglobulin Isotypes; Immunoglobulin M; Inner mitochondrial membrane; Integral Membrane Protein; Iron; Iron Overload; Knockout Mice; Lead; Light; Lipid Peroxidation; Lymphocyte; Lymphopoiesis; Lysine; Mitochondria; Peripheral; Proteins; Reactive Oxygen Species; Regulation; Role; Serum; Sulfur; Tetanus Helper Peptide; Transgenic Organisms; conditional knockout; ferrochelatase; functional disability; iron metabolism; stem cells; surrogate light chain

Iron homeostasis is critical for basic cellular functions and iron is used as a co-factor by many proteins that regulate transcription, proliferation and survival. Free iron is toxic to cells. Thus, iron homeostasis is tightly regulated. ABCB7 is an integral membrane protein found on mitochondrial inner membranes that belongs to the ABC (ATP-binding cassette) family of transporters. ABCB7 transports Fe-S-glutathione intermediates from the mitochondria to the cytoplasm for incorporation into ISCs (iron sulfur clusters). Inducible deletion of ABCB7 in Mx1-cre ABCB7 conditional knockout (cKO) mice resulted in rapid hematopoietic failure with multi-lineage defects in hematopoiesis. However, the function of ABCB7 in specific hematopoietic lineages has not been examined. We find that both mb1-cre ABCB7 conditional knockout (cKO) mice and CD2-icre ABCB7 cKO mice exhibit a severe block in B cell development with almost no IgM+ immature B cells produced. Deletion of ABCB7 using CD19-cre or CD23-cre had no effect on B cell development or peripheral B cell homeostasis, indicating a specific requirement for ABCB7 early in B cell development and demonstrating that ABCB7 is not simply required for survival. In mb1-cre or CD2-icre ABCB7 cKO mice, there is a decrease in B cell progenitors which express intracellular µHC, and those present are unable to downregulate the surrogate light chain genes. Iron is a co-factor for many enzymes which regulate chromatin accessibility, including the Tet family of dioxygenases and most of the histone lysine demethylases (KDMs). Thus, the absence of ABCB7 may disrupt the function of these enzymes, altering the ability to appropriately regulate chromatin accessibility as B lymphocytes progress through key developmental checkpoints. We hypothesize that disruption of iron homeostasis by deletion of ABCB7 in B cell progenitors leads to a block in their development through dysregulation of iron-dependent chromatin-modifying enzymes, which will be examined in this proposal.

铁稳态对于基本的细胞功能是至关重要的，并且铁被许多蛋白质用作辅助因子 调节转录、增殖和存活。游离铁对细胞有毒。因此，铁稳态是 严格监管。ABCB 7是在线粒体内膜上发现的一种完整的膜蛋白， 属于ABC（ATP结合盒）转运蛋白家族。ABCB 7转运Fe-S-谷胱甘肽 在一些实施方案中，铁硫簇是从线粒体到细胞质的中间体，用于并入ISC（铁硫簇）。 在Mx 1-cre ABCB 7条件性敲除（cKO）小鼠中诱导ABCB 7缺失导致快速的 具有造血中多谱系缺陷的造血衰竭。然而，ABCB 7在特定的 造血谱系尚未被研究。我们发现mb 1-cre ABCB 7条件性敲除（cKO） 小鼠和CD 2-icre ABCB 7 cKO小鼠表现出B细胞发育的严重阻滞，几乎没有IgM+ 未成熟的B细胞产生。用CD 19-cre或CD 23-cre缺失ABCB 7对B细胞无影响 发育或外周B细胞稳态，表明在B细胞早期对ABCB 7的特异性需求 这表明ABCB 7不仅仅是生存所必需的。mb 1-cre或CD 2-icre 在ABCB 7 cKO小鼠中，表达细胞内μHC的B细胞祖细胞减少， 不能下调替代轻链基因。铁是许多酶的辅因子， 调节染色质可及性，包括双加氧酶的泰特家族和大多数组蛋白赖氨酸 脱甲基酶（KDM）。因此，ABCB 7的缺失可能会破坏这些酶的功能，改变这些酶的功能。 当B淋巴细胞通过关键的发育过程时， 检查站我们推测，在B细胞祖细胞中，ABCB 7的缺失破坏了铁的稳态， 通过铁依赖性染色质修饰酶的失调导致其发育受阻， 这将在本提案中进行审查。