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HIV-1 Env induces pexophagy and an oxidative stress leading to uninfected CD4+ T cell death
Autophagy ( IF 14.6 ) Pub Date : 2020-10-19 , DOI: 10.1080/15548627.2020.1831814
Coralie F Daussy 1 , Mathilde Galais 1 , Baptiste Pradel 1 , Véronique Robert-Hebmann 1 , Sophie Sagnier 1 , Sophie Pattingre 2 , Martine Biard-Piechaczyk 1 , Lucile Espert 1
Affiliation  

ABSTRACT

The immunodeficiency observed in HIV-1-infected patients is mainly due to uninfected bystander CD4+ T lymphocyte cell death. The viral envelope glycoproteins (Env), expressed at the surface of infected cells, play a key role in this process. Env triggers macroautophagy/autophagy, a process necessary for subsequent apoptosis, and the production of reactive oxygen species (ROS) in bystander CD4+ T cells. Here, we demonstrate that Env-induced oxidative stress is responsible for their death by apoptosis. Moreover, we report that peroxisomes, organelles involved in the control of oxidative stress, are targeted by Env-mediated autophagy. Indeed, we observe a selective autophagy-dependent decrease in the expression of peroxisomal proteins, CAT and PEX14, upon Env exposure; the downregulation of either BECN1 or SQSTM1/p62 restores their expression levels. Fluorescence studies allowed us to conclude that Env-mediated autophagy degrades these entire organelles and specifically the mature ones. Together, our results on Env-induced pexophagy provide new clues on HIV-1-induced immunodeficiency.

Abbreviations: Ab: antibodies; AF: auranofin; AP: anti-proteases; ART: antiretroviral therapy; BafA1: bafilomycin A1; BECN1: beclin 1; CAT: catalase; CD4: CD4 molecule; CXCR4: C-X-C motif chemokine receptor 4; DHR123: dihydrorhodamine 123; Env: HIV-1 envelope glycoproteins; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GFP-SKL: GFP-serine-lysine-leucine; HEK: human embryonic kidney; HIV-1: type 1 human immunodeficiency virus; HTRF: homogeneous time resolved fluorescence; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NAC: N-acetyl-cysteine; PARP: poly(ADP-ribose) polymerase; PEX: peroxin; ROS: reactive oxygen species; siRNA: small interfering ribonucleic acid; SQSTM1/p62: sequestosome 1.



中文翻译:

HIV-1 Env 诱导 pexophagy 和氧化应激,导致未感染的 CD4+ T 细胞死亡

摘要

在 HIV-1 感染患者中观察到的免疫缺陷主要是由于未感染的旁观者 CD4 + T 淋巴细胞死亡。在受感染细胞表面表达的病毒包膜糖蛋白 (Env) 在此过程中起关键作用。Env 触发巨自噬/自噬,这是随后细胞凋亡所必需的过程,以及旁观者 CD4 +中活性氧 (ROS) 的产生T细胞。在这里,我们证明 Env 诱导的氧化应激是导致它们因细胞凋亡而死亡的原因。此外,我们报告过氧化物酶体,即参与控制氧化应激的细胞器,是 Env 介导的自噬的目标。事实上,我们观察到在 Env 暴露后,过氧化物酶体蛋白 CAT 和 PEX14 表达的选择性自噬依赖性降低。BECN1 或 SQSTM1/p62 的下调恢复了它们的表达水平。荧光研究让我们得出结论,Env 介导的自噬会降解这些整个细胞器,特别是成熟的细胞器。总之,我们关于 Env 诱导的 pexophagy 的结果为 HIV-1 诱导的免疫缺陷提供了新的线索。

缩写: Ab:抗体;AF:金诺芬;AP:抗蛋白酶;ART:抗逆转录病毒疗法;BafA 1:巴弗洛霉素 A 1;BECN1:beclin 1;CAT:过氧化氢酶;CD4:CD4分子;CXCR4:CXC基序趋化因子受体4;DHR123:二氢罗丹明 123;Env:HIV-1 包膜糖蛋白;GAPDH:3-磷酸甘油醛脱氢酶;GFP:绿色荧光蛋白;GFP-SKL:GFP-丝氨酸-赖氨酸-亮氨酸;HEK:人胚肾;HIV-1:1型人类免疫缺陷病毒;HTRF:均质时间分辨荧光;MAP1LC3/LC3:微管相关蛋白1轻链3;NAC:N-乙酰半胱氨酸;PARP:聚(ADP-核糖)聚合酶;PEX:过氧化物;ROS:活性氧;siRNA:小干扰核糖核酸;SQSTM1/p62:sequestosome 1。

更新日期:2020-10-19
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