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.

铁稳态对于基本细胞功能至关重要，铁被许多蛋白质用作辅助因子 调节转录、增殖和存活。因此，铁稳态是有毒的。 ABCB7 是一种在线粒体内膜上发现的整合膜蛋白。 ABCB7 属于 ABC（ATP 结合盒）转运蛋白家族，转运 Fe-S-谷胱甘肽。 从线粒体到细胞质的中间体并入 ISC（铁硫簇）。 Mx1-cre ABCB7 条件敲除 (cKO) 小鼠中 ABCB7 的诱导缺失导致快速 造血功能衰竭伴有多谱系造血缺陷 然而，ABCB7 的功能具有特异性。 我们尚未检查造血谱系，发现 mb1-cre ABCB7 条件性敲除 (cKO)。 小鼠和 CD2-icre ABCB7 cKO 小鼠表现出 B 细胞发育严重受阻，几乎没有 IgM+ 使用 CD19-cre 或 CD23-cre 删除 ABCB7 对 B 细胞没有影响。 发育或外周 B 细胞稳态，表明 B 细胞早期对 ABCB7 的特定需求 开发并证明 ABCB7 不仅仅是 mb1-cre 或 CD2-icre 生存所必需的。 ABCB7 cKO 小鼠，表达细胞内 µHC 的 B 细胞祖细胞减少，并且存在的 B 细胞祖细胞减少 无法下调替代轻链基因。铁是许多酶的辅助因子。 调节染色质可及性，包括双加氧酶 Tet 家族和大部分组蛋白赖氨酸 因此，ABCB7 的缺失可能会破坏这些酶的功能，从而改变 随着 B 淋巴细胞在关键发育过程中的进展，适当调节染色质可及性的能力 我们通过删除 B 细胞祖细胞中的 ABCB7 来对抗铁稳态的破坏。 通过铁依赖性染色质修饰酶的失调导致其发育受阻， 本提案将对此进行审查。