Peptide inhibition of p22phox and Rubicon interaction as a therapeutic strategy for septic shock
Peptide inhibition of p22phox and Rubicon interaction as a therapeutic strategy for septic shock
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DOI：
10.1016/j.biomaterials.2016.05.046
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发表时间：
2016-09-01
期刊：
影响因子：
14
通讯作者：
Yang, Chul-Su
中科院分区：
文献类型：
--
作者：
Kim, Ye-Ram;Koh, Hyun-Jung;Yang, Chul-Su
脓毒症是一种伴随严重感染的临床综合征，以全身炎症反应综合征（SIRS）为特征，是一种以全身炎症为特征的危及生命的疾病。微生物感染后，p22phox-gp91phox NADPH氧化酶（NOX）复合物产生活性氧（ROS），这对消除入侵微生物至关重要。然而，ROS的过量产生是脓毒症中一系列有害过程的关键因素。我们之前报道了自噬和吞噬机制之间的直接相互作用，证明Rubicon蛋白在微生物感染时与p22phox相互作用，促进p22phox-gp91phox NOX复合物的吞噬体运输，诱导ROS爆发，炎症细胞因子产生，从而具有有效的抗微生物活性。在这里，我们证明了N8肽，一个来自p22phox的n端8氨基酸肽，足以进行Rubicon相互作用，因此能够强有力地阻断Rubicon-p22phox相互作用，并深刻抑制ROS和炎症细胞因子的产生。因此，用Tat-N8肽或模拟N8肽的小分子治疗可显著降低盲肠结扎和穿刺引起的小鼠多微生物败血症的死亡率。这项研究展示了一种新的抗败血症治疗策略，通过阻断自噬和吞噬先天免疫机制之间的串扰，代表了迫切需要的治疗干预这种危及生命的SIRS的潜在范式转变。(C) 2016 Elsevier Ltd.版权所有。
Sepsis is a clinical syndrome that complicates severe infection and is characterized by the systemic inflammatory response syndrome (SIRS), is a life threatening disease characterized by inflammation of the entire body. Upon microbial infection, p22phox-gp91phox NADPH oxidase (NOX) complexes produce reactive oxygen species (ROS) that are critical for the elimination of invading microbes. However, excess production of ROS represents a key element in the cascade of deleterious processes in sepsis. We have previously reported direct crosstalk between autophagy and phagocytosis machineries by demonstrating that the Rubicon protein interacts with p22phox upon microbial infection, facilitating phagosomal trafficking of the p22phox-gp91phox NOX complex to induce a ROS burst, inflammatory cytokine production, and thereby, potent anti-microbial activities. Here, we showed N8 peptide, an N-terminal 8-amino acid peptide derived from p22phox, was sufficient for Rubicon interaction and thus, capable of robustly blocking the Rubicon-p22phox interaction and profoundly suppressing ROS and inflammatory cytokine production. Consequently, treatment with the Tat-N8 peptide or a N8 peptide-mimetic small-molecule dramatically reduced the mortality associated with Cecal-Ligation-and-Puncture-induced polymicrobial sepsis in mice. This study demonstrates a new anti-sepsis therapeutic strategy by blocking the crosstalk between autophagy and phagocytosis innate immunity machineries, representing a potential paradigm shift for urgently needed therapeutic intervention against this life-threatening SIRS. (C) 2016 Elsevier Ltd. All rights reserved.