Inhibition of the inflammatory response to stress by targeting interaction between PKR and its cellular activator PACT.
Inhibition of the inflammatory response to stress by targeting interaction between PKR and its cellular activator PACT.
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DOI：
10.1038/s41598-017-16089-8
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发表时间：
2017-11-23
影响因子：
4.6
通讯作者：
Meurs EF
中科院分区：
文献类型：
--
作者：
Dabo S;Maillard P;Collados Rodriguez M;Hansen MD;Mazouz S;Bigot DJ;Tible M;Janvier G;Helynck O;Cassonnet P;Jacob Y;Bellalou J;Gatignol A;Patel RC;Hugon J;Munier-Lehmann H;Meurs EF
PKR是一种参与调节整合应激反应（ISR）和促炎途径的细胞激酶。两个N-末端dsRNA结合结构域（DRBD）通过与dsRNA或PACT（另一种含DBD的细胞蛋白）相互作用来激活PKR。已经提出PKR和PACT在与神经退行性疾病相关的炎症过程中的作用，并引起了对药理学PKR抑制剂的兴趣。然而，PKR在炎症中的作用受到争议。我们确定了黄酮类化合物毛地黄黄酮作为PKR/PACT相互作用的抑制剂，在其DRBDs的水平上使用高通量筛选的化学库，通过均匀的时间分辨荧光。使用基于NanoLuc-Based蛋白质互补测定进一步验证了这一点。木犀草素抑制PKR磷酸化，ISR和诱导人THP 1巨噬细胞中的促炎细胞因子提交氧化应激和Toll样受体（TLR）激动剂。类似地，毛地黄黄酮抑制小鼠小胶质细胞巨噬细胞中促炎细胞因子的诱导。与此相反，毛地黄黄酮增加炎症体的激活，在PKR-独立的方式。总的来说，这些数据描述了PKR在炎症过程中对ISR和促炎细胞因子诱导的重要性。PKR的药理学抑制剂应与直接靶向炎性小体的药物联合使用。
PKR is a cellular kinase involved in the regulation of the integrative stress response (ISR) and pro-inflammatory pathways. Two N-terminal dsRNA Binding Domains (DRBD) are required for activation of PKR, by interaction with either dsRNA or PACT, another cellular DRBD-containing protein. A role for PKR and PACT in inflammatory processes linked to neurodegenerative diseases has been proposed and raised interest for pharmacological PKR inhibitors. However, the role of PKR in inflammation is subject to controversy. We identified the flavonoid luteolin as an inhibitor of the PKR/PACT interaction at the level of their DRBDs using high-throughput screening of chemical libraries by homogeneous time-resolved fluorescence. This was further validated using NanoLuc-Based Protein Complementation Assay. Luteolin inhibits PKR phosphorylation, the ISR and the induction of pro-inflammatory cytokines in human THP1 macrophages submitted to oxidative stress and toll-like receptor (TLR) agonist. Similarly, luteolin inhibits induction of pro-inflammatory cytokines in murine microglial macrophages. In contrast, luteolin increased activation of the inflammasome, in a PKR-independent manner. Collectively, these data delineate the importance of PKR in the inflammation process to the ISR and induction of pro-inflammatory cytokines. Pharmacological inhibitors of PKR should be used in combination with drugs targeting directly the inflammasome.
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DOI：
10.1016/s0006-291x(03)01318-4
发表时间：
2003-08-15
影响因子：
3.1
作者：
Jammi, NV;Whitby, LR;Beal, PA
通讯作者：
Beal, PA
DOI：
10.1073/pnas.82.13.4341
发表时间：
1985-01-01
影响因子：
11.1
作者：
LAURENT, AG;KRUST, B;HOVANESSIAN, AG
通讯作者：
HOVANESSIAN, AG
影响因子：
7.7
作者：
Nakamura T;Arduini A;Baccaro B;Furuhashi M;Hotamisligil GS
通讯作者：
Hotamisligil GS
影响因子：
3.5
作者：
Lee, Eun-Soo;Yoon, Cheol-Hee;Bae, Yong-Soo
通讯作者：
Bae, Yong-Soo
影响因子：
4.8
作者：
Bonnet, Marion C.;Daurat, Caroline;Meurs, Eliane F.
通讯作者：
Meurs, Eliane F.