Endogenous retrovirus-like proteins recruit UBQLN2 to stress granules and shape their functional biology

IF 12.5 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2025-07-18 DOI:10.1126/sciadv.adu6354

Harihar M. Mohan, Martin G. Fernandez, Camellia Huang, Rita Lin, Jaimie H. Ryou, Donald Seyfried, Nikolas Grotewold, Anna J. Barget, Alexandra M. Whiteley, Venkatesha Basrur, Shyamal Mosalaganti, Henry L. Paulson, Lisa M. Sharkey

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Abstract

The human genome is replete with sequences derived from foreign elements including endogenous retrovirus-like proteins of unknown function. Here, we show that UBQLN2, a ubiquitin-proteasome shuttle factor implicated in neurodegenerative diseases, is regulated by the linked actions of two retrovirus-like proteins, retrotransposon gag-like 8 (RTL8) and paternally expressed gene 10 (PEG10). RTL8 confers on UBQLN2 the ability to complex with and regulate PEG10. PEG10, a core component of stress granules, drives the recruitment of UBQLN2 to stress granules under various stress conditions but can only do so when RTL8 is present. Changes in UBQLN2, RTL8, or PEG10 levels further remodel the kinetics of stress granule disassembly and translation recovery. PEG10 also alters overall stress granule composition by incorporating select extracellular vesicle proteins. Within stress granules, PEG10 forms virus-like particles, underscoring the structural heterogeneity of this class of biomolecular condensates. Together, these results reveal an unexpected link between pathways of cellular proteostasis and endogenous retrovirus-like proteins.

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内源性逆转录病毒样蛋白招募UBQLN2来胁迫颗粒并塑造其功能生物学

人类基因组充满了来自外源元素的序列，包括内源性功能未知的逆转录病毒样蛋白。在这里，我们发现UBQLN2是一种与神经退行性疾病有关的泛素蛋白酶体穿梭因子，受两种逆转录病毒样蛋白，反转录转座子gag样8 （RTL8）和父本表达基因10 （PEG10）的联合作用调节。RTL8赋予UBQLN2与PEG10配合和调控的能力。PEG10是应力颗粒的核心成分，在各种应力条件下都能驱动UBQLN2向应力颗粒募集，但只有在RTL8存在的情况下才能实现。UBQLN2、RTL8或PEG10水平的变化进一步重塑了应力颗粒分解和翻译恢复的动力学。PEG10还通过结合选择的细胞外囊泡蛋白改变了整体应激颗粒的组成。在应力颗粒中，PEG10形成病毒样颗粒，强调了这类生物分子凝聚物的结构异质性。总之，这些结果揭示了细胞蛋白质停滞和内源性逆转录病毒样蛋白途径之间意想不到的联系。

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来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.