LIV-1 ZIP Ectodomain Shedding in Prion-Infected Mice Resembles Cellular Response to Transition Metal Starvation
LIV-1 ZIP Ectodomain Shedding in Prion-Infected Mice Resembles Cellular Response to Transition Metal Starvation
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DOI：
10.1016/j.jmb.2012.06.003
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发表时间：
2012-09-28
影响因子：
5.6
通讯作者：
Schmitt-Ulms, Gerold
中科院分区：
文献类型：
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作者：
Ehsani, Sepehr;Salehzadeh, Ashkan;Schmitt-Ulms, Gerold
我们最近记录了ZIP（Zrt-、Irt样蛋白）锌转运蛋白（LZT）的LIV-1亚家族成员与细胞朊病毒蛋白（PrPC）的共纯化，随后确定了朊病毒基因家族起源于祖先LZT基因。在这里，我们开始解决是否LZTs的研究可以揭示朊病毒蛋白在健康和疾病的生物学。从朊病毒感染的小鼠中异常LZT免疫反应条带的观察开始，随后的细胞生物学分析揭示了ZIP10（LZT成员）和朊病毒蛋白的令人惊讶的协调生物学，其涉及响应于对细胞外二价阳离子环境的操纵的N-糖基化和内蛋白水解的改变。饥饿细胞的锰或锌，但不是铜，导致脱落的N1片段的PrPC和胞外域的ZIP10。对于ZIP10，这种翻译后生物学受到其PrP样胞外域与其C-末端多跨膜结构域内的保守金属配位位点之间的相互作用的影响。过渡金属饥饿诱导的ZIP10切割可以通过不成熟的N-糖基化特征与靶向相同位点的组成型切割区分。这项工作的数据提供了迄今为止被忽视的分子生物学的第一个一瞥，联系PrP的LZT表兄弟，并建议锰或锌饥饿可能有助于小鼠朊病毒疾病的病因。(C)2012爱思唯尔有限公司保留所有权利。
We recently documented the co-purification of members of the LIV-1 subfamily of ZIP (Zrt-, Irt-like Protein) zinc transporters (LZTs) with the cellular prion protein (PrPC) and, subsequently, established that the prion gene family descended from an ancestral LZT gene. Here, we begin to address whether the study of LZTs can shed light on the biology of prion proteins in health and disease. Starting from an observation of an abnormal LZT immunoreactive band in prion-infected mice, subsequent cell biological analyses uncovered a surprisingly coordinated biology of ZIP10 (an LZT member) and prion proteins that involves alterations to N-glycosylation and endoproteolysis in response to manipulations to the extracellular divalent cation milieu. Starving cells of manganese or zinc, but not copper, causes shedding of the N1 fragment of PrPC and of the ectodomain of ZIP10. For ZIP10, this posttranslational biology is influenced by an interaction between its PrP-like ectodomain and a conserved metal coordination site within its C-terminal multi-spanning transmembrane domain. The transition metal starvation-induced cleavage of ZIP10 can be differentiated by an immature N-glycosylation signature from a constitutive cleavage targeting the same site. Data from this work provide a first glimpse into a hitherto neglected molecular biology that ties PrP to its LZT cousins and suggest that manganese or zinc starvation may contribute to the etiology of prion disease in mice. (C) 2012 Elsevier Ltd. All rights reserved.