HIV-1 Nef与APOL1-G1协同诱导hiv相关肾脏疾病的肾细胞死亡

IF 3.3 3区 医学 Q2 CELL BIOLOGY
Disease Models & Mechanisms Pub Date : 2025-07-01 Epub Date: 2025-08-01 DOI:10.1242/dmm.052178
Jun-Yi Zhu, Yulong Fu, Joyce van de Leemput, Jing Yu, Jinliang Li, Patricio E Ray, Zhe Han
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引用次数: 0

摘要

携带两个APOL1风险等位基因(RA) - G1或G2的人患人类免疫缺陷病毒(HIV)相关肾病(HIVAN)的风险更高。然而,目前尚不清楚编码蛋白(APOL1-RA)和HIV-1 Nef是否相互作用诱导足细胞死亡。在这里,我们产生了在肾细胞(相当于哺乳动物足细胞)中特异性表达APOL1-G1(来自患有HIVAN的儿童)和HIV-1 nef的转基因果蝇,并评估了它们对肾细胞过滤结构和功能的单独和联合影响。我们发现HIV-1 Nef与APOL1-G1协同作用,导致肾细胞结构和功能缺陷,Nef加剧了APOL1-G1诱导的细胞器酸化缺陷和自噬减少。HIV-1 Nef和APOL1-G1之间的协同作用是建立在它们对内质网(ER)应激升高、触发肾细胞功能障碍并最终导致细胞死亡的联合作用之上的。因此,我们确定内质网应激是HIV-1 Nef和APOL1-G1协同诱导肾细胞死亡的会聚点。鉴于果蝇肾细胞和人类足细胞之间的高度相似性,我们的研究结果表明内质网应激是HIV-1和apol1相关肾病的新治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
HIV-1 Nef synergizes with APOL1-G1 to induce nephrocyte cell death in HIV-related kidney diseases.

People carrying two APOL1 risk alleles (RA) - G1 or G2 - are at greater risk of developing human immunodeficiency virus (HIV)-associated nephropathy (HIVAN). However, it remains unclear whether the encoded protein(s) (APOL1-RA) and HIV-1 Nef interact to induce podocyte cell death. Here, we generated transgenic flies that express APOL1-G1 (derived from a child with HIVAN) and HIV-1 nef specifically in the nephrocytes, the fly equivalent of mammalian podocytes, and assessed their individual and combined effects on the nephrocyte filtration structure and function. We found that HIV-1 Nef acts in synergy with APOL1-G1, resulting in nephrocyte structural and functional defects, and that Nef exacerbates the organelle acidification defects and autophagy reduction induced by APOL1-G1. The synergy between HIV-1 Nef and APOL1-G1 is built on their joint effects on elevating endoplasmic reticulum (ER) stress, triggering nephrocyte dysfunction and, ultimately, cell death. Thus, we identified ER stress as the converging point for the synergy between HIV-1 Nef and APOL1-G1 in inducing nephrocyte cell death. Given the high similarity between Drosophila nephrocytes and human podocytes, our findings suggest ER stress as a new therapeutic target for HIV-1- and APOL1-associated nephropathies.

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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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