Conquering the complex world of human septins: implications for health and disease.
Conquering the complex world of human septins: implications for health and disease.
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DOI：
10.1111/j.1399-0004.2010.01392.x
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发表时间：
2010-06
影响因子：
3.5
通讯作者：
Petty EM
中科院分区：
文献类型：
--
作者：
Peterson EA;Petty EM
Septins是一种高度保守的丝状蛋白，最初在发芽酵母中鉴定，后来在所有真核生物中发现。葡聚糖能结合和降解GTP，这与其形成葡聚糖六聚体和功能蛋白相互作用有着内在的联系。人类Septin家族由14个基因座SEPT1-SEPT14组成，编码数十种不同的Septin蛋白。它们的中心GTP酶和多碱性结构域高度保守，但在N端和/或C端存在分歧。产生不同异构体的机制尚不清楚，但人们可以假设，使用不同的启动子和/或替代剪接可能会产生这些变体。根据组织表达及其相互作用伙伴的不同，Septins具有不同的细胞功能。到目前为止，已发现的功能包括细胞分裂、染色体分离、蛋白质支架、细胞极性、运动性、膜动力学、囊泡运输、胞吐、细胞凋亡和DNA损伤反应。它们的表达受到严格的调控，以维持适当的细丝组装和正常的细胞功能。这些蛋白的突变或表达变化与多种癌症和神经系统疾病有关。由于白血病(MLL)中实体肿瘤易位(MLL)的表达变化，导致了Septins与癌症的关联。Septins的表达变化也与阿尔茨海默氏症和帕金森氏病等神经系统疾病以及视网膜疾病、丙型肝炎、精子发生和李斯特菌感染有关。在常染色体显性遗传性神经性肌营养不良(HNA)中发现了SEPT9的致病突变。在过去的十年中，人类对Septin的研究已经确定了它们在细胞生物学和人类疾病中的重要性。进一步的功能表征对于我们理解它们可能的诊断、预后和治疗应用是至关重要的。
Septins are highly conserved filamentous proteins first characterized in budding yeast and subsequently identified in all eukaryotes. Septins can bind and hydrolyze GTP which is intrinsically related to their formation of septin hexamers and functional protein interactions. The human septin family is composed of 14 loci, SEPT1-SEPT14, which encodes dozens of different septin proteins. Their central GTPase and polybasic domain regions are highly conserved but they diverge in their N-terminus and/or C-terminus. The mechanism by which the different isoforms are generated is not yet well understood, but one can hypothesize that the use of different promoters and/or alternative splicing could give rise to these variants. Septins perform diverse cellular functions according to tissue expression and their interacting partners. Functions identified to date include cell division, chromosome segregation, protein scaffolding, cellular polarity, motility, membrane dynamics, vesicle trafficking, exocytosis, apoptosis, and DNA damage response. Their expression is tightly regulated to maintain proper filament assembly and normal cellular functions. Alteration of these proteins, by mutation or expression changes, has been associated with a variety of cancers and neurological diseases. The association of septins with cancer results from expression alterations in solid tumorsor translocations in leukemias (MLL). Expression changes in septins have also been associated with neurological conditions such as Alzheimer’s and Parkinson’s disease, as well as retinopathies, Hepatitis C, spermatogenesis and Listeria infection. Pathogenic mutations of SEPT9 were identified in the autosomal dominant neurological disorder Hereditary Neuralgic Amyotrophy (HNA). Human septin research over the past decade has established their importance in cell biology and human disease. Further functional characterization of septins is crucial to our understanding of their possible diagnostic, prognostic, and therapeutic applications.
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