Analysis of Prelamin A Biogenesis Reveals the Nucleus to be a CaaX Processing Compartment
Analysis of Prelamin A Biogenesis Reveals the Nucleus to be a CaaX Processing Compartment
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DOI：
10.1091/mbc.e08-07-0704
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发表时间：
2008-12-01
影响因子：
3.3
通讯作者：
Michaelis, Susan
中科院分区：
文献类型：
--
作者：
Barrowman, Jemima;Hamblet, Corinne;Michaelis, Susan
蛋白质通过靶向、保留和检索信号建立并维持独特的细胞内定位，确保大多数蛋白质主要驻留在一个细胞位置。参与核纤层蛋白A成熟的酶对这种模式提出了挑战。核纤层蛋白A首先合成为74 kDa前体，前核纤层蛋白A，具有C-末端CaaX基序，并经历一系列翻译后修饰，包括CaaX加工（法尼基化，aaX切割和羧基甲基化），然后通过Zmpste 24进行内切蛋白水解切割。不能裂解前层蛋白A导致早衰症和相关的过早衰老病症。有证据表明，前层蛋白A直接输入到细胞核中进行加工。特别地，加工酶已被证明存在于细胞溶质中（法尼基转移酶），或者是ER膜蛋白（Zmpste 24，Rce 1和Icmt），其活性位点面向细胞溶质。在这里，我们重新检查了前层蛋白A加工的细胞位点，并表明哺乳动物和酵母加工酶Zmpste 24和Icmt表现出双重定位的内核膜，以及ER膜。我们的研究结果揭示了细胞核是CaaX加工的生理相关位置，并提供了对破坏性早老性疾病中心蛋白质生物学的深入了解。
Proteins establish and maintain a distinct intracellular localization by means of targeting, retention, and retrieval signals, ensuring most proteins reside predominantly in one cellular location. The enzymes involved in the maturation of lamin A present a challenge to this paradigm. Lamin A is first synthesized as a 74-kDa precursor, prelamin A, with a C-terminal CaaX motif and undergoes a series of posttranslational modifications including CaaX processing (farnesylation, aaX cleavage and carboxylmethylation), followed by endoproteolytic cleavage by Zmpste24. Failure to cleave prelamin A results in progeria and related premature aging disorders. Evidence suggests prelamin A is imported directly into the nucleus where it is processed. Paradoxically, the processing enzymes have been shown to reside in the cytosol (farnesyltransferase), or are ER membrane proteins (Zmpste24, Rce1, and Icmt) with their active sites facing the cytosol. Here we have reexamined the cellular site of prelamin A processing, and show that the mammalian and yeast processing enzymes Zmpste24 and Icmt exhibit a dual localization to the inner nuclear membrane, as well as the ER membrane. Our findings reveal the nucleus to be a physiologically relevant location for CaaX processing, and provide insight into the biology of a protein at the center of devastating progeroid diseases.