Mutation in human CLPX elevates levels of δ-aminolevulinate synthase and protoporphyrin IX to promote erythropoietic protoporphyria
Mutation in human CLPX elevates levels of δ-aminolevulinate synthase and protoporphyrin IX to promote erythropoietic protoporphyria
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DOI：
10.1073/pnas.1700632114
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发表时间：
2017-09-19
影响因子：
11.1
通讯作者：
Paw, Barry H.
中科院分区：
文献类型：
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作者：
Yien, Yvette Y.;Ducamp, Sarah;Paw, Barry H.
血红素生物合成酶基因的功能丧失突变可引起先天性卟啉症，目前已描述了八种形式。卟啉症的遗传外显率在临床上是可变的，强调了其他致病基因、贡献基因和修饰基因的作用。我们之前发现线粒体 AAA+ 解折叠酶 ClpX 通过激活 d-氨基乙酰丙酸合酶 (ALAS) 来促进血红素生物合成，而 ALAS 催化血红素合成的第一步。据报道，CLPX 还可介导血红素诱导的 ALAS 周转。在这里，我们报告了人类 CLPX 的 ATP 酶活性位点的显性突变，第 14 页。 Gly298Asp，导致血红素生物合成中间体原卟啉 IX (PPIX) 的病理性积累。红系细胞中 PPIX 的积累会促进受影响家族的红细胞生成性原卟啉症 (EPP)。 CLPX 中的突变使其 ATP 酶活性失活，导致突变体和 WT 原聚体共同组装，形成活性降低的酶。低活性 CLPX 的存在会增加 ALAS 的翻译后稳定性，导致 ALAS 蛋白和 ALA 水平升高，导致 PPIX 异常积累。因此，我们的结果确定了 EPP 发展的另一个分子机制，并进一步加深了我们对 CLPX 控制血红素代谢的多种机制的理解。
Loss-of-function mutations in genes for heme biosynthetic enzymes can give rise to congenital porphyrias, eight forms of which have been described. The genetic penetrance of the porphyrias is clinically variable, underscoring the role of additional causative, contributing, and modifier genes. We previously discovered that the mitochondrial AAA+ unfoldase ClpX promotes heme biosynthesis by activation of d-aminolevulinate synthase (ALAS), which catalyzes the first step of heme synthesis. CLPX has also been reported to mediate heme-induced turnover of ALAS. Here we report a dominant mutation in the ATPase active site of human CLPX, p. Gly298Asp, that results in pathological accumulation of the heme biosynthesis intermediate protoporphyrin IX (PPIX). Amassing of PPIX in erythroid cells promotes erythropoietic protoporphyria (EPP) in the affected family. The mutation in CLPX inactivates its ATPase activity, resulting in coassembly of mutant and WT protomers to form an enzyme with reduced activity. The presence of low-activity CLPX increases the posttranslational stability of ALAS, causing increased ALAS protein and ALA levels, leading to abnormal accumulation of PPIX. Our results thus identify an additional molecular mechanism underlying the development of EPP and further our understanding of the multiple mechanisms by which CLPX controls heme metabolism.