A Nesprin-4/kinesin-1 cargo model for nuclear positioning in cochlear outer hair cells.
A Nesprin-4/kinesin-1 cargo model for nuclear positioning in cochlear outer hair cells.
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DOI：
10.3389/fcell.2022.974168
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发表时间：
2022
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
核定位对于许多细胞类型的功能是重要的，并且由细胞骨架元件和核骨架蛋白的相互作用介导。Nesprin蛋白是核骨架和细胞骨架（LINC）复合体连接子的一部分，已被证明参与多种细胞类型的核定位。内耳中的外毛细胞（OHC）是专门的感觉上皮细胞，其利用躯体电运动来放大耳蜗中的听觉信号。最近，Nesprin-4（由Syne 4编码）被证明在OHC的核定位中起着至关重要的作用。人类和小鼠中的Syne 4缺乏导致OHC核的错误定位和细胞死亡，从而导致耳聋。然而，尚不清楚Nesprin-4如何介导细胞核的位置，以及哪些其他分子组分参与了这一过程。在这里，我们表明，Nesprin-4和微管运动驱动蛋白-1的相互作用是由一个保守的4个氨基酸基序介导的。使用体内腺相关病毒基因递送，我们表明这种相互作用对于小鼠的核定位和听力至关重要。OHC的核错误定位和细胞死亡与听力和电运动的发生一致，并且仅限于外毛细胞，而不是内毛细胞。C. Nesprin-4的elegans功能同源物，Nesprin-83，使用类似的基序来介导迁移核和驱动蛋白-1之间的相互作用。总的来说，我们的研究结果表明，OHC需要独特的细胞机械适当的核定位在发病时的电活动。这种机制依赖于Nesprin-4和驱动蛋白-1马达之间的相互作用，支持用于核定位的微管货物模型。
Nuclear positioning is important for the functionality of many cell types and is mediated by interactions of cytoskeletal elements and nucleoskeleton proteins. Nesprin proteins, part of the linker of nucleoskeleton and cytoskeleton (LINC) complex, have been shown to participate in nuclear positioning in multiple cell types. Outer hair cells (OHCs) in the inner ear are specialized sensory epithelial cells that utilize somatic electromotility to amplify auditory signals in the cochlea. Recently, Nesprin-4 (encoded by Syne4) was shown to play a crucial role in nuclear positioning in OHCs. Syne4 deficiency in humans and mice leads to mislocalization of the OHC nuclei and cell death resulting in deafness. However, it is unknown how Nesprin-4 mediates the position of the nucleus, and which other molecular components are involved in this process. Here, we show that the interaction of Nesprin-4 and the microtubule motor kinesin-1 is mediated by a conserved 4 amino-acid motif. Using in vivo AAV gene delivery, we show that this interaction is critical for nuclear positioning and hearing in mice. Nuclear mislocalization and cell death of OHCs coincide with the onset of hearing and electromotility and are solely restricted to outer, but not inner, hair cells. Likewise, the C. elegans functional homolog of Nesprin-4, UNC-83, uses a similar motif to mediate interactions between migrating nuclei and kinesin-1. Overall, our results suggest that OHCs require unique cellular machinery for proper nuclear positioning at the onset of electromotility. This machinery relies on the interaction between Nesprin-4 and kinesin-1 motors supporting a microtubule cargo model for nuclear positioning.
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影响因子：
8.8
作者：
Chiba, Kyoko;Ori-McKenney, Kassandra M.;Niwa, Shinsuke;McKenney, Richard J.
通讯作者：
McKenney, Richard J.
DOI：
10.1083/jcb.201004118
发表时间：
2010-10-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Fridolfsson HN;Starr DA
通讯作者：
Starr DA
影响因子：
10.7
作者：
Minh BQ;Nguyen MA;von Haeseler A
通讯作者：
von Haeseler A
影响因子：
5.4
作者：
Ashmore, Jonathan
通讯作者：
Ashmore, Jonathan
影响因子：
3.3
作者：
Farboud, Behnom;Severson, Aaron F.;Meyer, Barbara J.
通讯作者：
Meyer, Barbara J.