Role of a Small Molecule in the Modulation of Cell Death Signal Transduction Pathways.
Role of a Small Molecule in the Modulation of Cell Death Signal Transduction Pathways.
复制标题
DOI：
10.1021/acsinfecdis.8b00231
复制
发表时间：
2018-12-14
影响因子：
5.3
通讯作者：
Martchenko M
中科院分区：
文献类型：
--
作者：
Hartmann S;Nusbaum DJ;Kim K;Alameh S;Ho CC;Cruz RL;Levitin A;Bradley KA;Martchenko M
炎性小体激活半胱天冬酶-1以响应来自病原体和其他危险刺激的分子信号，作为先天免疫应答的一部分。先前的一项研究发现了一种小分子4-氟-N '-[1-（2-吡啶基）亚乙基]苯甲酰肼，我们将其命名为DN 1，它可以降低炭疽致死毒素（LT）的细胞毒性。我们确定，DN 1保护细胞不受LT浓度的影响，并降低了额外的细菌外毒素和几种病毒的致病性。使用LT的细胞毒性途径，我们表明，DN 1不阻止LT的内化和催化活性，或半胱天冬酶-1激活。此外，DN 1不影响宿主组织蛋白酶B的蛋白水解活性，这有助于毒素进入细胞质。PubChem生物活性列出了两种G蛋白偶联受体（GPCR），1型血管紧张素II受体和爱帕琳受体，作为DN 1的靶点。抑制磷脂酰肌醇3-激酶，磷脂酶C和蛋白激酶B，这是下游的GPCR信号，协同DN 1在保护细胞免受LT。我们假设DN 1介导的GPCR拮抗调节信号转导途径，诱导细胞状态，减少LT诱导的细胞凋亡下游的caspase-1激活。DN 1还降低了果蝇对毒素相关细菌感染的易感性。未来的实验将旨在进一步表征DN 1如何调节信号转导途径，以抑制LT敏感性巨噬细胞中的细胞死亡。DN 1代表了一种新型的化学探针，用于研究介导细胞死亡的宿主细胞机制。
Inflammasomes activate caspase-1 in response to molecular signals from pathogens and other danger stimuli as a part of the innate immune response. A previous study discovered a small-molecule, 4-fluoro-N’-[1-(2-pyridinyl)ethylidene]benzohydrazide, which we named DN1, that reduces the cytotoxicity of anthrax lethal toxin (LT). We determined that DN1 protected cells irrespectively of LT concentration and reduced the pathogenicity of an additional bacterial exotoxin and several viruses. Using the LT cytotoxicity pathway, we show that DN1 does not prevent LT internalization and catalytic activity, or caspase-1 activation. Moreover, DN1 does not affect the proteolytic activity of host cathepsin B, which facilitates the cytoplasmic entry of toxins. PubChem Bioactivities lists two G protein-coupled receptors (GPCR), type-1 angiotensin II receptor and apelin receptor, as targets of DN1. The inhibition of phosphatidylinositol 3-kinase, phospholipase C, and protein kinase B, which are downstream of GPCR signaling, synergized with DN1 in protecting cells from LT. We hypothesize that DN1-mediated antagonism of GPCRs modulates signal transduction pathways to induce a cellular state that reduces LT-induced pyroptosis downstream of caspase-1 activation. DN1 also reduced the susceptibility of Drosophila melanogaster to toxin-associated bacterial infections. Future experiments will aim to further characterize how DN1 modulates signal transduction pathways to inhibit pyroptotic cell death in LT-sensitive macrophages. DN1 represents a novel chemical probe to investigate host cellular mechanisms that mediate cell death in response to pathogenic agents.
登录
查看更多内容
影响因子：
3.7
作者：
Haspot F;Lavault A;Sinzger C;Laib Sampaio K;Stierhof YD;Pilet P;Bressolette-Bodin C;Halary F
通讯作者：
Halary F
DOI：
10.1073/pnas.0431098100
发表时间：
2003-04-29
影响因子：
11.1
作者：
Scobie, HM;Rainey, GJA;Young, JAT
通讯作者：
Young, JAT
影响因子：
2.9
作者：
Miller, CJ;Elliott, JL;Collier, RJ
通讯作者：
Collier, RJ
影响因子：
3.6
作者：
MILNE, JC;BLANKE, SR;COLLIER, RJ
通讯作者：
COLLIER, RJ
DOI：
10.1155/2012/935970
发表时间：
2012-01-01
期刊：
International journal of evolutionary biology
影响因子：
--
作者：
Ma, Junjie;Benson, Andrew K;Harshman, Lawrence G
通讯作者：
Harshman, Lawrence G