Lamin B receptor regulates the growth and maturation of myeloid progenitors via its sterol reductase domain: implications for cholesterol biosynthesis in regulating myelopoiesis.
Lamin B receptor regulates the growth and maturation of myeloid progenitors via its sterol reductase domain: implications for cholesterol biosynthesis in regulating myelopoiesis.
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DOI：
10.4049/jimmunol.1003804
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发表时间：
2012-01-01
期刊：
影响因子：
--
通讯作者：
Gaines P
中科院分区：
文献类型：
--
作者：
Subramanian G;Chaudhury P;Malu K;Fowler S;Manmode R;Gotur D;Zwerger M;Ryan D;Roberti R;Gaines P
核纤层蛋白 B 受体 (LBR) 是一种双功能核膜蛋白，具有 N 端核纤层蛋白 B 和染色质结合域以及 C 端甾醇 Δ14 还原酶域。 LBR 表达在中性粒细胞分化过程中增加，表达缺陷会破坏 Pelger-Huët 异常的中性粒细胞核分叶特征。因此，LBR 在调节骨髓分化中发挥着关键作用，但 LBR 的两个功能域如何支持这一作用目前尚不清楚。我们之前发现了源自EML-ic/ic细胞的早幼粒细胞（EPRO细胞）的异常增殖和功能成熟缺陷，EML-ic/ic细胞是缺乏Lbr表达的鱼鳞病（ic）骨髓的骨髓模型。在这里，我们提供了新的证据，证明胆固醇生物合成对骨髓细胞生长很重要，并得到 Lbr 甾醇还原酶结构域的支持。胆固醇生物合成抑制剂引起 EML 细胞的生长抑制，这种抑制在 EPRO 细胞中增加，而缺乏 Lbr 的细胞在两个阶段都表现出完全的生长停滞。野生型中性粒细胞成熟期间脂质产生增加，但 ic/ic 细胞表现出脂质和胆固醇产生水平不足。 EML-ic/ic 细胞中全长 Lbr 的异位表达可挽救胆固醇饥饿条件下的核分叶和生长停滞。脂质的产生也得到了挽救，呼吸爆发不足也得到了纠正。在 ic/ic 细胞中仅表达 Lbr 的 C 端甾醇还原酶结构域也改善了这些表型。我们的数据支持这样的结论：LBR 的甾醇 Δ14 还原酶结构域在胆固醇生物合成中发挥着关键作用，并且该过程对于骨髓细胞生长和功能成熟至关重要。
Lamin B receptor (LBR) is a bifunctional nuclear membrane protein with N-terminal lamin B and chromatin binding domains plus a C-terminal sterol Δ14 reductase domain. LBR expression increases during neutrophil differentiation and deficient expression disrupts neutrophil nuclear lobulation characteristic of Pelger-Huët anomaly. Thus LBR plays a critical role in regulating myeloid differentiation, but how the two functional domains of LBR support this role is currently unclear. We previously identified abnormal proliferation and deficient functional maturation of promyelocytes (EPRO cells) derived from EML-ic/ic cells, a myeloid model of ichthyosis (ic) bone marrow that lacks Lbr expression. Here we provide new evidence that cholesterol biosynthesis is important to myeloid cell growth and is supported by the sterol reductase domain of Lbr. Cholesterol biosynthesis inhibitors caused growth inhibition of EML cells that increased in EPRO cells, whereas cells lacking Lbr exhibited complete growth arrest at both stages. Lipid production increased during wild-type neutrophil maturation, but ic/ic cells exhibited deficient levels of lipid and cholesterol production. Ectopic expression of a full length Lbr in EML-ic/ic cells rescued both nuclear lobulation and growth arrest in cholesterol starvation conditions. Lipid production also was rescued, and a deficient respiratory burst was corrected. Expression of just the C-terminal sterol reductase domain of Lbr in ic/ic cells also improved each of these phenotypes. Our data support the conclusion that the sterol Δ14 reductase domain of LBR plays a critical role in cholesterol biosynthesis, and that this process is essential to both myeloid cell growth and functional maturation.
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影响因子：
6.5
作者：
Clutterbuck, RD;Millar, BC;Millar, JL
通讯作者：
Millar, JL
影响因子：
4.8
作者：
Guichard, C;Pedruzzi, E;Elbim, C
通讯作者：
Elbim, C
影响因子：
30.8
作者：
Hoffmann, K;Dreger, CK;Sperling, K
通讯作者：
Sperling, K
影响因子：
4.8
作者：
Barabé, F;Paré, G;Naccache, PH
通讯作者：
Naccache, PH
DOI：
10.1073/pnas.95.14.8181
发表时间：
1998-07-07
影响因子：
11.1
作者：
Fitzky, BU;Witsch-Baumgartner, M;Moebius, FF
通讯作者：
Moebius, FF