Lps2:: a new locus required for responses to lipopolysaccharide, revealed by germline mutagenesis and phenotypic screening
Lps2:: a new locus required for responses to lipopolysaccharide, revealed by germline mutagenesis and phenotypic screening
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DOI：
10.1179/096805103225001459
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发表时间：
2003-01-01
期刊：
影响因子：
--
通讯作者：
Beutler, B
中科院分区：
文献类型：
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作者：
Hoebe, K;Du, X;Beutler, B
正向和反向遗传技术均已用于定义哺乳动物脂多糖（LPS）受体的成分。 TLR4 通过正向遗传学方法鉴定为经典 Lps 基因座的产物，是哺乳动物 LPS 受体唯一已知的跨膜成分。基因敲除工作还证实，LPS 信号转导需要 CD14、MD-2 以及部分 MyD88、IRAK4 和 TRAF-6 的完整性。然而，没有理由相信这些是构成受体/转导装置的唯一蛋白质。为了检查其他蛋白质可能参与其中的可能性，我们启动了一项诱变计划，其中使用 N-乙基-N-亚硝基脲 (ENU) 在小鼠中诱导种系突变，并筛选个体动物的巨噬细胞对 LPS 做出反应的能力。我们现在报道了一个新基因座 Lps2 的存在，它是响应 LPS 产生 TNF 所必需的。我们鉴定出的 Lps2 突变是共显性的，其表型效应与 LpS(d) 相似，并且不代表已知编码“核心”LPS 信号装置的任何基因的新等位基因。 Lps2 突变并不排除肽聚糖或未甲基化 DNA 引发的信号传导。因此，遗传数据表明，LPS 受体复合物中至少有一个“缺失”的成分尚未被发现。
Both forward and reverse genetic techniques have been used to define components of the mammalian lipopolysaccharide (LPS) receptor. TLR4, identified by a forward genetic approach as the product of the classical Lps locus, is the only known transmembrane component of the mammalian LPS receptor. Gene knockout work has also established that LPS signal transduction requires the integrity of CD14, MD-2, and, in part, MyD88, IRAK4, and TRAF-6. However, there is no reason to believe that these are the only proteins that make up the receptor/transducer apparatus. To examine the possibility that other proteins may be involved, we initiated a mutagenesis program, in which germline mutations are induced in mice using N-ethyl-N-nitrosourea (ENU), and macrophages from individual animals are screened for their competence to respond to LPS. We now report the existence of a new locus, Lps2, which is required for TNF production in response to LPS. The Lps2 mutation that we have identified is co-dominant, is similar in phenotypic effect to LpS(d), and does not represent a novel allele of any of the genes that are known to encode the 'core' LPS signaling apparatus. The Lps2 mutation does not preclude signaling initiated by peptidoglycan or unmethylated DNA. Hence, genetic data suggest that there is at least one 'missing' component of the LPS receptor complex that has yet to be found.