SUT-2 potentiates tau-induced neurotoxicity in Caenorhabditis elegans
SUT-2 potentiates tau-induced neurotoxicity in Caenorhabditis elegans
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DOI：
10.1093/hmg/ddp099
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发表时间：
2009-05-15
影响因子：
3.5
通讯作者：
Kraemer, Brian C.
中科院分区：
文献类型：
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作者：
Guthrie, Chris R.;Schellenberg, Gerard D.;Kraemer, Brian C.
人tau在秀丽隐杆线虫神经元中的表达引起聚集的tau的积累，导致神经变性和不协调的运动。我们使用这种人类tau蛋白病疾病模型来筛选tau神经毒性所需的基因。sut-2基因座中的隐性功能丧失突变抑制Unc表型、tau聚集和由人tau引起的神经退行性变化。我们克隆了sut-2基因，发现它编码一种在动物门中保守的CCCH锌指蛋白的新亚型。SUT-2与哺乳动物SUT-2（MSUT-2）具有显著的同一性。为了鉴定SUT-2相互作用蛋白，我们进行了酵母双杂交筛选，发现SUT-2与唯一的C. HOOK蛋白家族成员。同样，SUT-2在体外蛋白结合测定中结合ZYG-12。此外，ZYG-12的缺失导致SUT-2蛋白的显著上调，支持SUT-2和ZYG-12之间的连接。人类基因组编码ZYG-12的三个同源物：HOOK 1，HOOK 2和HOOK 3。其中，SUT-2的人直系同源物（MSUT-2）仅结合HOOK 2，表明SUT-2和HOOK家族蛋白之间的相互作用在动物门中是保守的。在C. elegans可能提出了新的神经保护策略，能够阻止tau蛋白病疾病中的tau蛋白发病机制。
Expression of human tau in Caenorhabditis elegans neurons causes accumulation of aggregated tau leading to neurodegeneration and uncoordinated movement. We used this model of human tauopathy disorders to screen for genes required for tau neurotoxicity. Recessive loss-of-function mutations in the sut-2 locus suppress the Unc phenotype, tau aggregation and neurodegenerative changes caused by human tau. We cloned the sut-2 gene and found it encodes a novel sub-type of CCCH zinc finger protein conserved across animal phyla. SUT-2 shares significant identity with the mammalian SUT-2 (MSUT-2). To identify SUT-2 interacting proteins, we conducted a yeast two hybrid screen and found SUT-2 binds to ZYG-12, the sole C. elegans HOOK protein family member. Likewise, SUT-2 binds ZYG-12 in in vitro protein binding assays. Furthermore, loss of ZYG-12 leads to a marked upregulation of SUT-2 protein supporting the connection between SUT-2 and ZYG-12. The human genome encodes three homologs of ZYG-12: HOOK1, HOOK2 and HOOK3. Of these, the human ortholog of SUT-2 (MSUT-2) binds only to HOOK2 suggesting the interaction between SUT-2 and HOOK family proteins is conserved across animal phyla. The identification of sut-2 as a gene required for tau neurotoxicity in C. elegans may suggest new neuroprotective strategies capable of arresting tau pathogenesis in tauopathy disorders.