奥地利维也纳医科大学Tim Clausen团队的研究开发出了分裂位点E3连接酶机制使ZNFX1能够泛素化并将单链RNA聚集成泛素包被的核蛋白颗粒。该研究于2025年8月27日发表于国际一流学术期刊《细胞》杂志上。
该研究团队证明单链RNA通过促进沿核酸轨迹易位的ZNFX1亚基的二聚化来刺激E3活性。并列的E3结构域相互补充，导致ZNFX1自身泛素化，并参与RNA分子，同时将核酸凝聚成致密的核蛋白颗粒。课题组发现ZNFX1的E3连接酶活性在免疫应答中保护细胞，并提出由ZNFX1形成的泛素包被颗粒代表了调节细胞中外源和宿主RNA的古老机制的一部分。
据了解，真核细胞以多层免疫反应来对抗细胞内病原体。泛素连接酶ZNFX1已经成为一个关键的但鲜为人知的玩家，调节免疫反应，同时保护免受RNA病毒主题。他们的研究揭示了ZNFX1的分子机制，由作为核酸传感器的解旋酶和具有分裂活性位点的非传统E3模块的联合活性介导。
附：英文原文
Title: A split-site E3 ligase mechanism enables ZNFX1 to ubiquitinate and cluster single-stranded RNA into ubiquitin-coated nucleoprotein particles
Author: Daniel B. Grabarczyk, Eric J. Aird, Vanessa Reznikow, Paul C. Kirchgatterer, Julian F. Ehrmann, Robert Kurzbauer, Lillie E. Bell, Max J. Kellner, Ritika Aggarwal, Alexander Schleiffer, Victoria Faas, Luiza Deszcz, Anton Meinhart, Gijs A. Versteeg, Josef M. Penninger, Lukas S. Stelzl, Moritz M. Gaidt, Ingrid Tessmer, Jacob E. Corn, Tim Clausen
Issue&Volume: 2025-08-27
Abstract: Eukaryotic cells use a multi-layered immune response to combat intracellular pathogens. The ubiquitin ligase ZNFX1 has emerged as a crucial yet little understood player that regulates the immune response while protecting against RNA viruses. Our study unveils the molecular mechanism of ZNFX1, mediated by the joint activity of a helicase serving as a nucleic acid sensor and a non-conventional E3 module featuring a split active site. We demonstrate that single-stranded RNA stimulates E3 activity by fostering dimerization of ZNFX1 subunits that translocate along nucleic acid tracks. Juxtaposed E3 domains complement each other, leading to the ubiquitination of ZNFX1 itself and engaged RNA molecules, while clustering nucleic acids into dense nucleoprotein particles. We show that the E3 ligase activity of ZNFX1 protects cells during an immune response and propose that ubiquitin-coated particles formed by ZNFX1 represent part of an ancient mechanism to regulate both foreign and host RNA in the cell.
DOI: 10.1016/j.cell.2025.08.006
Source: https://www.cell.com/cell/abstract/S0092-8674(25)00920-1