TOM1 G307D变体损害与TOLLIP的相互作用,自噬体-溶酶体融合和先天免疫调节。

IF 3.3 3区 医学 Q2 CELL BIOLOGY
Disease Models & Mechanisms Pub Date : 2025-09-01 Epub Date: 2025-09-30 DOI:10.1242/dmm.052140
Heljä K M Lång, Tiffany G Roach, Maarit Hölttä, Salla Keskitalo, Markku Varjosalo, Kaarina Heiskanen, Megan V Collins, Mikko R J Seppänen, Daniel G S Capelluto, Elina Ikonen, Samppa J Ryhänen
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引用次数: 0

摘要

最近发现的一种内体衔接蛋白TOM1的G307D变异可导致严重的早发性多器官自身免疫和联合免疫缺陷。通过结合生物物理、生化和细胞培养实验,我们发现该变异导致TOM1和TOLLIP(另一种参与货物运输和先天免疫调节的接头蛋白)之间相互作用的缺陷。G307D变体削弱了TOM1降低TOLLIP的磷脂酰肌醇3-磷酸结合的能力,这是两种蛋白的货物运输承诺的重要调节机制。我们使用TOM1 G307D患者细胞进行的实验表明,由于自噬体-溶酶体融合缺陷,该变异影响自噬,被视为对氨基酸饥饿和自噬体积累的加重反应。此外,炎症通路在TOM1 G307D患者细胞中表现出过度激活。我们的数据表明,TOM1和TOLLIP之间的相互作用在人体免疫系统的调节中发挥作用,并突出了基本细胞功能(如货物运输)在控制免疫应答中的重要性。我们的研究也为TOM1致病变异患者的免疫调节和干细胞治疗的注意事项提供了见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A TOM1 variant impairs interaction with TOLLIP, autophagosome-lysosome fusion and regulation of innate immunity.

A recently described G307D variant of the endosomal adaptor protein TOM1 causes severe early-onset multiorgan autoimmunity and combined immunodeficiency. By combining biophysical, biochemical and cell culture experiments, we show that the variant causes a defect in the interaction between TOM1 and TOLLIP, another adaptor protein involved in cargo trafficking and regulation of innate immunity. The G307D variant impairs the ability of TOM1 to reduce TOLLIP phosphatidylinositol 3-phosphate binding, an important regulatory mechanism for cargo trafficking commitment for both proteins. Our experiments using TOM1 G307D patient cells suggested that the variant affects autophagy, seen as an aggravated response to amino acid starvation and accumulation of autophagosomes due to autophagosome-lysosome fusion defect. In addition, inflammatory pathways showed excessive activation in TOM1 G307D patient cells. Our data suggest that the interaction between TOM1 and TOLLIP has a role in the regulation of the human immune system and highlight the importance of fundamental cellular functions, such as cargo trafficking, in controlling immune responses. Our study also provides insights into the caveats of immunomodulatory and stem cell therapies in patients with TOM1 pathogenic variants.

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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
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