Individual Expression of Hepatitis A Virus 3C Protease Induces Ferroptosis in Human Cells In Vitro.
Individual Expression of Hepatitis A Virus 3C Protease Induces Ferroptosis in Human Cells In Vitro.
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DOI：
10.3390/ijms22157906
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发表时间：
2021-07-23
影响因子：
5.6
通讯作者：
Demidyuk IV
中科院分区：
文献类型：
--
作者：
Komissarov AA;Karaseva MA;Roschina MP;Shubin AV;Lunina NA;Kostrov SV;Demidyuk IV
调节性细胞死亡（Regulated Cell Death，RCD）是几乎所有生物共同的基本过程，对动物和人类的发育和组织稳态至关重要。多种分子可诱导RCD，包括许多病毒蛋白水解酶。迄今为止，许多数据表明，小RNA病毒3C蛋白酶可以诱导RCD。在大多数报道的情况下，这些蛋白酶诱导经典的半胱天冬酶依赖性细胞凋亡。与此相反，人类甲型肝炎病毒3C蛋白酶（3Cpro）最近已被证明会导致半胱天冬酶非依赖性细胞死亡伴随着以前未描述的功能。在这里，我们在HEK293，HeLa和A549人类细胞系中表达3Cpro，以使用流式细胞术和荧光显微镜从形态学和生物化学上表征3Cpro诱导的细胞死亡。我们发现，死亡细胞表现出坏死样的形态学变化，包括质膜透化，线粒体电位的损失，以及线粒体和核肿胀。此外，我们发现，3Cpro诱导的细胞死亡被铁凋亡抑制剂有效地阻断，并伴随着强烈的脂质过氧化。总之，这些结果表明，3Cpro在人细胞中单独表达时诱导铁凋亡。这是第一次证明蛋白水解酶可以诱导铁凋亡，最近发现和积极研究的RCD类型。
Regulated cell death (RCD) is a fundamental process common to nearly all living beings and essential for the development and tissue homeostasis in animals and humans. A wide range of molecules can induce RCD, including a number of viral proteolytic enzymes. To date, numerous data indicate that picornaviral 3C proteases can induce RCD. In most reported cases, these proteases induce classical caspase-dependent apoptosis. In contrast, the human hepatitis A virus 3C protease (3Cpro) has recently been shown to cause caspase-independent cell death accompanied by previously undescribed features. Here, we expressed 3Cpro in HEK293, HeLa, and A549 human cell lines to characterize 3Cpro-induced cell death morphologically and biochemically using flow cytometry and fluorescence microscopy. We found that dead cells demonstrated necrosis-like morphological changes including permeabilization of the plasma membrane, loss of mitochondrial potential, as well as mitochondria and nuclei swelling. Additionally, we showed that 3Cpro-induced cell death was efficiently blocked by ferroptosis inhibitors and was accompanied by intense lipid peroxidation. Taken together, these results indicate that 3Cpro induces ferroptosis upon its individual expression in human cells. This is the first demonstration that a proteolytic enzyme can induce ferroptosis, the recently discovered and actively studied type of RCD.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
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作者：
Glickstein, H;Ben El, R;Cabantchik, ZI
通讯作者：
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