A point mutation in the murine Hem1 gene reveals an essential role for Hematopoietic Protein 1 in lymphopoiesis and innate immunity
A point mutation in the murine Hem1 gene reveals an essential role for Hematopoietic Protein 1 in lymphopoiesis and innate immunity
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DOI：
10.1084/jem.20080340
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发表时间：
2008-11-24
影响因子：
15.3
通讯作者：
Iritani, Brian M.
中科院分区：
文献类型：
--
作者：
Park, Heon;Staehling-Hampton, Karen;Iritani, Brian M.
HEM1(造血蛋白1)是细胞质接头蛋白Hem家族中的一种造血细胞特异性成员。盘基网柄菌、黑腹果蝇和秀丽线虫中的hem1同源基因对细胞骨架重组、胚胎细胞迁移和形态发生都是必不可少的。然而，哺乳动物hem1的体内功能尚不清楚。在小鼠身上使用化学诱变策略来识别与免疫细胞功能有关的新基因，我们定位地克隆了hem1基因中的一个无义突变。HEM1缺乏导致F-肌动蛋白聚合缺陷和淋巴细胞和中性粒细胞肌动蛋白封顶，这是由于RAC控制的肌动蛋白调节波蛋白复合体的丢失造成的。在处于CD4(-)CD8(-)(双阴性)到CD4(+)CD8(+)(双阳性)细胞阶段的hem1缺陷小鼠中，T细胞的发育受到干扰，而T细胞的激活和黏附能力受到损害。缺乏hem1的中性粒细胞不能对趋化剂做出反应，并且缺乏吞噬细菌的能力。值得注意的是，一些依赖RAC的功能，如Th1分化和核因子-kappa B(NF-kappa B)依赖的促炎细胞因子转录在hem1缺陷小鼠中正常进行，而Th17细胞的产生增加。这些结果表明，通过控制导致细胞骨架重组的不同途径，hem1对造血细胞的发育、功能和动态平衡是必不可少的，而依赖于核因子-kappa B的转录不依赖于hem1和F-肌动蛋白聚合。
Hem1 (Hematopoietic protein 1) is a hematopoietic cell-specific member of the Hem family of cytoplasmic adaptor proteins. Orthologues of Hem1 in Dictyostelium discoideum, Drosophila melanogaster, and Caenorhabditis elegans are essential for cytoskeletal reorganization, embryonic cell migration, and morphogenesis. However, the in vivo functions of mammalian Hem1 are not known. Using a chemical mutagenesis strategy in mice to identify novel genes involved in immune cell functions, we positionally cloned a nonsense mutation in the Hem1 gene. Hem1 deficiency results in defective F-actin polymerization and actin capping in lymphocytes and neutrophils caused by loss of the Rac-controlled actin-regulatory WAVE protein complex. T cell development is disrupted in Hem1-deficient mice at the CD4(-)CD8(-) (double negative) to CD4(+)CD8(+) (double positive) cell stages, whereas T cell activation and adhesion are impaired. Hem1-deficient neutrophils fail to migrate in response to chemotactic agents and are deficient in their ability to phagocytose bacteria. Remarkably, some Rac-dependent functions, such as Th1 differentiation and nuclear factor kappa B (NF-kappa B)-dependent transcription of proinflammatory cytokines proceed normally in Hem1-deficient mice, whereas the production of Th17 cells are enhanced. These results demonstrate that Hem1 is essential for hematopoietic cell development, function, and homeostasis by controlling a distinct pathway leading to cytoskeletal reorganization, whereas NF-kappa B-dependent transcription proceeds independently of Hem1 and F-actin polymerization.