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α-辅肌动蛋白4介导SEPT14突变诱导的精子头部缺陷。

ACTN4 Mediates SEPT14 Mutation-Induced Sperm Head Defects.

作者信息

Lin Yu-Hua, Huang Chia-Yen, Ke Chih-Chun, Wang Ya-Yun, Lai Tsung-Hsuan, Liu Hsuan-Che, Ku Wei-Chi, Chan Chying-Chyuan, Lin Ying-Hung

机构信息

Department of Chemistry, Fu Jen Catholic University, New Taipei City 242, Taiwan.

Division of Urology, Department of Surgery, Cardinal Tien Hospital, New Taipei City 231, Taiwan.

出版信息

Biomedicines. 2020 Nov 19;8(11):518. doi: 10.3390/biomedicines8110518.

DOI:10.3390/biomedicines8110518
PMID:33228246
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7699536/
Abstract

Septins (SEPTs) are highly conserved GTP-binding proteins and the fourth component of the cytoskeleton. Polymerized SEPTs participate in the modulation of various cellular processes, such as cytokinesis, cell polarity, and membrane dynamics, through their interactions with microtubules, actin, and other cellular components. The main objective of this study was to dissect the molecular pathological mechanism of mutation-induced sperm head defects. To identify SEPT14 interactors, co-immunoprecipitation (co-IP) and nano-liquid chromatography-mass spectrometry/mass spectrometry were applied. Immunostaining showed that SEPT14 was significantly localized to the manchette structure. The SEPT14 interactors were identified and classified as (1) SEPT-, (2) microtubule-, (3) actin-, and (4) sperm structure-related proteins. One interactor, ACTN4, an actin-holding protein, was selected for further study. Co-IP experiments showed that SEPT14 interacts with ACTN4 in a male germ cell line. SEPT14 also co-localized with ACTN4 in the perinuclear and manchette regions of the sperm head in early elongating spermatids. In the cell model, mutated SEPT14 disturbed the localization pattern of ACTN4. In a clinical aspect, sperm with mutant SEPT14, SEPT14 (p.Ala123Thr), and SEPT14 (p.Ile333Thr), have mislocalized and fragmented ACTN4 signals. Sperm head defects in donors with SEPT14 mutations are caused by disruption of the functions of ACTN4 and actin during sperm head formation.

摘要

Septins（SEPTs）是高度保守的GTP结合蛋白，也是细胞骨架的第四种组分。聚合的SEPTs通过与微管、肌动蛋白及其他细胞成分相互作用，参与各种细胞过程的调节，如胞质分裂、细胞极性和膜动力学。本研究的主要目的是剖析突变诱导的精子头部缺陷的分子病理机制。为了鉴定SEPT14相互作用蛋白，采用了免疫共沉淀（co-IP）和纳米液相色谱-质谱联用技术。免疫染色显示SEPT14显著定位于精（子）颈部结构。鉴定出SEPT14相互作用蛋白并将其分为（1）SEPT相关、（2）微管相关、（3）肌动蛋白相关和（4）精子结构相关蛋白。选择其中一个相互作用蛋白ACTN4（一种肌动蛋白结合蛋白）进行进一步研究。免疫共沉淀实验表明SEPT14在雄性生殖细胞系中与ACTN4相互作用。在早期伸长精子细胞中，SEPT14也与ACTN4在精子头部的核周和精（子）颈部区域共定位。在细胞模型中，突变的SEPT14扰乱了ACTN4的定位模式。在临床方面，携带突变SEPT14、SEPT14（p.Ala123Thr）和SEPT14（p.Ile333Thr）的精子，其ACTN4信号定位错误且碎片化。携带SEPT14突变的供体的精子头部缺陷是由精子头部形成过程中ACTN4和肌动蛋白功能的破坏所致。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/75b6/7699536/bd4698ea4be6/biomedicines-08-00518-g007.jpg
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