哈佛医学院Alan Brown小组取得一项新突破。他们的最新研究提出了从纤毛中获取多泛素化蛋白的保守机制。该项研究成果发表在2025年8月20日出版的《细胞》上。

使用多学科方法，课题组证明了CFAP36（一种以前未知功能的保守纤毛蛋白）和ARL3（一种参与纤毛进口的GTPase）的复合物结合多泛素化蛋白并将它们连接到逆行IFT序列。CFAP36设计了一种巧合检测机制，可以同时结合两个仅在逆行列车中可访问的IFT亚基。耗尽CFAP36会在纤毛中积累K63连接的泛素，并破坏依赖于泛素化受体的刺猬信号通路。这些发现促进了他们对泛素介导的蛋白质转运和纤毛稳态的理解，并证明了IFT列车的结构变化如何实现货物选择性。

据介绍，蛋白质在纤毛内的时空分布受鞭毛内运输（IFT）的调节，其中分子序列在细胞体和纤毛之间穿梭。这一过程的缺陷损害了各种信号转导途径和引起纤毛病。虽然K63连接的泛素化似乎触发了纤毛的蛋白质输出，但多泛素化蛋白与IFT耦合的机制尚不清楚。

附：英文原文

Title: A conserved mechanism for the retrieval of polyubiquitinated proteins from cilia

Author: Sven M. Lange, Jeremy A. Bennett, Robyn J. Eisert, Alan Brown

Issue&Volume: 2025-08-20

Abstract: The temporospatial distribution of proteins within cilia is regulated by intraflagellar transport (IFT), wherein molecular trains shuttle between the cell body and cilium. Defects in this process impair various signal-transduction pathways and cause ciliopathies. Although K63-linked ubiquitination appears to trigger protein export from cilia, the mechanisms coupling polyubiquitinated proteins to IFT remain unclear. Using a multidisciplinary approach, we demonstrate that a complex of CFAP36, a conserved ciliary protein of previously unknown function, and ARL3, a GTPase involved in ciliary import, binds polyubiquitinated proteins and links them to retrograde IFT trains. CFAP36 uses a coincidence detection mechanism to simultaneously bind two IFT subunits accessible only in retrograde trains. Depleting CFAP36 accumulates K63-linked ubiquitin in cilia and disrupts hedgehog signaling, a pathway reliant on the retrieval of ubiquitinated receptors. These findings advance our understanding of ubiquitin-mediated protein transport and ciliary homeostasis and demonstrate how structural changes in IFT trains achieve cargo selectivity.

DOI: 10.1016/j.cell.2025.07.043

Source: https://www.cell.com/cell/abstract/S0092-8674(25)00865-7