Role of Septins in Organelle Transfer

Septins 在细胞器转移中的作用

• 批准号: 7985809
• 负责人: ALAN Michael TARTAKOFF
• 金额: $ 30.62万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7985809
• 关键词: Actins; Animals; Biology; Cell Nucleus; Cells; Characteristics; Complex; Cytoplasm; Data; Daughter; Developmental Cell Biology; Disease; Ensure; Eukaryotic Cell; Exclusion; Exocytosis; Intermediate Filaments; Investigation; Lead; Learning; Membrane Proteins; Mitochondria; Mitotic Cell Cycle; Modification; Mothers; Neck; Nuclear Envelope; Organelles; Pharmaceutical Preparations; Polyribosomes; Positioning Attribute; Property; Role; Saccharomyces cerevisiae; Structure; Time; Vacuole; Yeasts; cell cortex; macromolecule; mitochondrial genome; mutant; novel; particle; prototype; public health relevance; spindle pole body; zygote

DESCRIPTION (provided by applicant): Accurate compartmentation/positioning of macromolecules and organelles is essential in eukaryotic cells. This proposal is concerned with a non-membranous barrier that subdivides the cytoplasm of yeast zygotes into regions of distinct parental origin. Examples of fibrous "zones- of-exclusion" have previously been described in the cytoplasm of animal cells, some of which include intermediate filaments or actin. None is nearly as amenable to analysis as the zygote midzone complex (ZMC) that we have detected and will investigate in S. cerevisiae. The ZMC includes septins and is reminiscent of septin-containing structures at the bud neck that lie between the mother and daughter during the mitotic cell cycle. A Checkpoint for Redistribution of Mitochondria: Preliminary data lead to the hypothesis that the ZMC delays fusion of parental mitochondria and therefore ensures uniparental inheritance of the mitochondrial genome, as has been observed. To evaluate this hypothesis, we will 1) Learn whether septins in the ZMC have the dynamic properties that are required, and 2) Determine whether uniparental inheritance of the mitochondrial genome is compromised in septin mutants. A Checkpoint for Redistribution of Polysomes: To determine whether the ZMC is responsible for the delay in redistribution of polysomes, we will inquire whether the timing of their redistribution reflects 1) Their size, 2) Functionality of septins, or 3) Contact between nuclei (and spindle pole bodies), as is suggested by our Preliminary Data. Generality of Function: To further understand the scope of importance of the ZMC we will learn whether it governs the redistribution of novel particles in the cytoplasm, limits flux of membrane proteins of the cell cortex and nuclear envelope, and is responsible for the observation that parental vacuoles do not exchange components with each other in early zygotes. Given the apparent similarity to the bud neck as well as preliminary observations, we will determine whether the ZMC delimits a cortical zone within which exocytosis occurs. We will also learn whether septins of the ZMC undergo characteristic covalent modifications and whether these modifications are essential for the organization and functions of the ZMC. The final part of the proposal concerns identification of the target of a drug, forchlorfenuron that reversibly alters the structures of septin assemblages and interrupts redistribution of mitochondria in zygotes. Since this drug also perturbs animal cell septins, identification of its target will open unanticipated avenues of investigation related to septin biology. PUBLIC HEALTH RELEVANCE: The partition which we will investigate provides a prototype of barriers that subcompartmentalize regions of the cytoplasm of eukaryotic cells. Our studies will help understand these very general principles, help elucidate functions of septins which are implicated in several diseases, clarify issues which are central to developmental cell biology and inheritance of the mitochondrial genome, and initiate the investigation of novel checkpoints that govern the distributions of organelles.

描述（由申请人提供）：在真核细胞中必不可少的大分子和细胞器的准确隔室化/定位。该提议与非膜屏障有关，该屏障将酵母菌的细胞质细胞细化为独特的父母起源区域。先前在动物细胞的细胞质中已经描述了纤维“排斥区域”的实例，其中一些包括中间细丝或肌动蛋白。我们已经检测到并将在酿酒酵母中进行调查的合子中区络合物（ZMC）几乎不像分析。 ZMC包括septins，让人联想到有丝分裂细胞周期中母女之间含有Septin的结构。线粒体重新分布的检查点：初步数据导致假设ZMC延迟了父母线粒体的融合，因此确保了线粒体基因组的单亲遗传，如所观察到的那样。为了评估这一假设，我们将1）了解ZMC中的septins是否具有所需的动态特性，2）确定线粒体基因组的单亲遗传是否在Septin突变体中受到损害。重新分布多个多个的检查点：为了确定ZMC是否负责延迟多聚体的重新分布，我们将询问其重新分布的时间是否反映了1）siptins的大小，或者3）核的功能，或3）核（和脊柱螺旋极）之间的接触，如我们的预言所示。功能的通用性：为了进一步了解ZMC的重要性范围，我们将了解它是否控制了细胞质中新型颗粒的重新分布，限制了细胞皮质和核包膜的膜蛋白的通量，并负责遵守父母液泡不会在Zygotes早期与其他人交换成分。 鉴于与芽颈以及初步观察的明显相似性，我们将确定ZMC是否划定了发生胞吐作用的皮质区域。我们还将了解ZMC的septins是否经历特征共价修改，以及这些修改是否对ZMC的组织和功能至关重要。 该提案的最后一部分涉及对药物的靶标的识别，即氯氟氟龙的靶标可逆地改变septin组合的结构，并中断合子中线粒体的重新分布。由于该药物也使动物细胞隔蛋白散布，因此对其靶标的识别将开放与隔丁生物学有关的意外研究途径。 公共卫生相关性：我们将研究的分区提供了一个障碍的原型，该障碍物将真核细胞细胞质区域的各个区域化。我们的研究将有助于理解这些非常一般的原理，有助于阐明隔蛋白的功能，这些功能与几种疾病有关，阐明了对发育细胞生物学的核心和线粒体基因组的遗传核心的问题，并启动了控制细胞器分布的新检查点的研究。