Winkler Brennan, Lerner Kasey, Lipschutz Joshua H
Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.
Department of Medicine, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, USA.
Ren Fail. 2025 Dec;47(1):2519832. doi: 10.1080/0886022X.2025.2519832. Epub 2025 Jun 23.
The primary cilium is an organelle found on different cell types in many organs, and is important for human health including the kidney. Diseases due to abnormal or absent cilia are termed ciliopathies and ADPKD is one of the most common ciliopathies and the fourth leading cause of ESKD. The mechanisms of how primary cilia work remain incompletely understood. One particular axis of ciliary function that is especially unclear is the role of the highly-conserved eight-subunit exocyst trafficking complex, which is critically involved in transporting proteins from the trans-Golgi network to the cilium. The goal of this review article is to cover key aspects of exocyst function, how these are known to or are predicted to impinge on ciliary function, and to point out areas that need further research. The exocyst has been shown to be regulated by many different small GTPases of the Rho, Ral, Rab, and Arf families which likely give the exocyst specificity of function. The exocyst has been implicated in several intracellular signaling pathways involving the cilium including the MAPK and phosphoinositide pathways. The exocyst and its regulators have also been found in urinary extracellular vesicles suggesting that the exocyst may be involved in 'urocrine' signaling and repair following AKI. There is an urgent need to develop new strategies to address exocyst function in the context of cilia, which will greatly benefit our understanding of cilia as well as how disrupted exocyst function in cilia leads to disease, which, in turn, should lead to novel therapeutics.
原发性纤毛是一种存在于许多器官中不同细胞类型上的细胞器，对包括肾脏在内的人体健康至关重要。由于纤毛异常或缺失导致的疾病被称为纤毛病，常染色体显性多囊肾病（ADPKD）是最常见的纤毛病之一，也是终末期肾病（ESKD）的第四大主要病因。原发性纤毛的工作机制仍未完全清楚。纤毛功能中一个特别不清楚的特定轴是高度保守的八亚基外排复合体的作用，该复合体在将蛋白质从反式高尔基体网络运输到纤毛的过程中起关键作用。这篇综述文章的目的是涵盖外排复合体功能的关键方面，以及已知或预计这些方面如何影响纤毛功能，并指出需要进一步研究的领域。外排复合体已被证明受Rho、Ral、Rab和Arf家族的许多不同小GTP酶调节，这些小GTP酶可能赋予外排复合体功能特异性。外排复合体与涉及纤毛的几种细胞内信号通路有关，包括丝裂原活化蛋白激酶（MAPK）和磷酸肌醇通路。在外泌体中也发现了外排复合体及其调节因子，这表明外排复合体可能参与急性肾损伤（AKI）后的“尿分泌”信号传导和修复。迫切需要制定新策略来研究纤毛背景下的外排复合体功能，这将极大地有助于我们理解纤毛，以及纤毛中外排复合体功能紊乱如何导致疾病，进而带来新的治疗方法。
