N-terminal functional domain of Gasdermin A3 regulates mitochondrial homeostasis via mitochondrial targeting.
N-terminal functional domain of Gasdermin A3 regulates mitochondrial homeostasis via mitochondrial targeting.
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DOI：
10.1186/s12929-015-0152-0
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发表时间：
2015-06-24
影响因子：
11
通讯作者：
Yang LT
中科院分区：
文献类型：
--
作者：
Lin PH;Lin HY;Kuo CC;Yang LT
表皮形成了一个关键的屏障，由精心策划的增殖、分化和细胞死亡程序来维持。扰乱这一周转过程的基因突变可能会导致皮肤病。人 GASDERMIN A (GSDMA) 在胃癌细胞系中经常被沉默，据报道其过度表达可诱导细胞凋亡。在遗传关联研究中，GSDMA 也与气道高反应性有关。 GSDMA 在皮肤中的功能是通过小鼠 Gasdermin A3 (Gsdma3) 的显性突变推断的，该突变会导致皮肤炎症和脱发。然而，Gsdma3突变的常染色体显性机制和Gsdma3的作用模式仍未得到解答。我们证明了 Gsdma3 在调节线粒体氧化应激方面的新功能。我们发现 Gsdma3 受到分子内折回抑制的调节，而分子内折回抑制会被 C 端结构域的显性突变所破坏。 Gsdma3 未掩蔽的 N 端结构域与 Hsp90 结合，并通过线粒体输入受体 Tom70 递送至线粒体，与线粒体伴侣 Trap1 相互作用，导致线粒体活性氧 (ROS) 产生增加、线粒体膜电位耗散和线粒体通透性转变 (MPT)。 Gsdma3 C 端结构域的过度表达以及线粒体易位、ROS 产生和 MPT 孔开放的药理学干预减轻了 Gsdma3 突变体诱导的细胞死亡。我们的结果表明，Gsdma3 C 端结构域的基因突变是功能获得性突变，它揭示了 Gsdma3 N 端功能结构域。 Gsdma3 通过线粒体靶向调节线粒体氧化应激。由于线粒体 ROS 已被证明可以促进表皮分化，因此我们假设 Gsdma3 通过影响线粒体来调节角质形成细胞对分化和细胞死亡信号的环境依赖性反应。本文的在线版本 (doi:10.1186/s12929-015-0152-0) 包含补充材料，可供授权用户使用。
The epidermis forms a critical barrier that is maintained by orchestrated programs of proliferation, differentiation, and cell death. Gene mutations that disturb this turnover process may cause skin diseases. Human GASDERMIN A (GSDMA) is frequently silenced in gastric cancer cell lines and its overexpression has been reported to induce apoptosis. GSDMA has also been linked with airway hyperresponsiveness in genetic association studies. The function of GSDMA in the skin was deduced by dominant mutations in mouse gasdermin A3 (Gsdma3), which caused skin inflammation and hair loss. However, the mechanism for the autosomal dominance of Gsdma3 mutations and the mode of Gsdma3’s action remain unanswered. We demonstrated a novel function of Gsdma3 in modulating mitochondrial oxidative stress. We showed that Gsdma3 is regulated by intramolecular fold-back inhibition, which is disrupted by dominant mutations in the C-terminal domain. The unmasked N-terminal domain of Gsdma3 associates with Hsp90 and is delivered to mitochondrial via mitochondrial importer receptor Tom70, where it interacts with the mitochondrial chaperone Trap1 and causes increased production of mitochondrial reactive oxygen species (ROS), dissipation of mitochondrial membrane potential, and mitochondrial permeability transition (MPT). Overexpression of the C-terminal domain of Gsdma3 as well as pharmacological interventions of mitochondrial translocation, ROS production, and MPT pore opening alleviate the cell death induced by Gsdma3 mutants. Our results indicate that the genetic mutations in the C-terminal domain of Gsdma3 are gain-of-function mutations which unmask the N-terminal functional domain of Gsdma3. Gsdma3 regulates mitochondrial oxidative stress through mitochondrial targeting. Since mitochondrial ROS has been shown to promote epidermal differentiation, we hypothesize that Gsdma3 regulates context-dependent response of keratinocytes to differentiation and cell death signals by impinging on mitochondria. The online version of this article (doi:10.1186/s12929-015-0152-0) contains supplementary material, which is available to authorized users.
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Gsdma3 基因是诱导小鼠毛囊周期中细胞凋亡驱动的退行期所必需的
影响因子：
2.3
作者：
Lei, Mingxing;Gao, Xiang;Lian, Xiaohua
通讯作者：
Lian, Xiaohua
影响因子：
6.5
作者：
Lunny, DP;Weed, E;Porter, RM
通讯作者：
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影响因子：
2.5
作者：
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通讯作者：
Shiroishi, T
DOI：
10.1080/10253890701314863
发表时间：
2007-11-01
影响因子：
2.3
作者：
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通讯作者：
Esposito, F.
影响因子：
6.5
作者：
Ruge, Fiona;Glavini, Aikaterini;Porter, Rebecca M.
通讯作者：
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