Genome-Wide RNAi Screen Identifies Regulators of Cardiomyocyte Necrosis.,ACS Pharmacology & Translational Science

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Genome-Wide RNAi Screen Identifies Regulators of Cardiomyocyte Necrosis.
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2019-09-04 , DOI: 10.1021/acsptsci.9b00052
Zhaokang Cheng ₁ , Matthew Combs ₂ , Qiang Zhu ₂ , Peng Xia ₁ , Zachary Opheim ₂ , Joel Parker _{2,

2} , Christopher P Mack _{2,

2} , Joan M Taylor _{2,

2}

Affiliation

Regulation of cellular death is central to nearly all physiological routines and is dysregulated in virtually all diseases. Cell death occurs by two major processes, necrosis which culminates in a pervasive inflammatory response and apoptosis which is largely immunologically inert. As necrosis has long been considered an accidental, unregulated form of cellular death that occurred in response to a harsh environmental stimulus, it was largely ignored as a clinical target. However, recent elegant studies suggest that certain forms of necrosis can be reprogrammed. However, scant little is known about the molecules and pathways that orchestrate calcium-overload-induced necrosis, a main mediator of ischemia/reperfusion (IR)-induced cardiomyocyte cell death. To rectify this critical gap in our knowledge, we performed a novel genome-wide siRNA screen to identify modulators of calcium-induced necrosis in human muscle cells. Our screen identified multiple molecular circuitries that either enhance or inhibit this process, including lysosomal calcium channel TPCN1, mitophagy mediatorTOMM7, Ran-binding protein RanBP9, Histone deacetylase HDAC2, chemokine CCL11, and the Arp2/3 complex regulator glia maturation factor-γ (GMFG). Notably, a number of druggable enzymes were identified, including the proteasome β5 subunit (encoded by PSMB5 gene), which controls the proteasomal chymotrypsin-like peptidase activity. Such findings open up the possibility for the discovery of pharmacological interventions that could provide therapeutic benefits to patients affected by myriad disorders characterized by excessive (or too little) necrotic cell loss, including but not limited to IR injury in the heart and kidney, chronic neurodegenerative disorders, muscular dystrophies, sepsis, and cancers.

中文翻译：

全基因组RNAi筛选可识别心肌细胞坏死的调节因子。

细胞死亡的调节对于几乎所有生理程序都是至关重要的，并且在几乎所有疾病中均失调。细胞死亡通过两个主要过程发生，坏死最终导致普遍的炎症反应，而凋亡在很大程度上是免疫惰性的。长期以来，坏死一直被认为是偶然的，不受管制的细胞死亡形式，是由于强烈的环境刺激而发生的，因此在很大程度上它被忽略为临床目标。但是，最近的研究表明，某些形式的坏死可以重新编程。然而，对协调钙超载引起的坏死（缺血/再灌注（IR）引起的心肌细胞死亡的主要媒介）的分子和途径知之甚少。为了纠正我们在知识方面的这一严重差距，我们进行了新型的全基因组siRNA筛选，以鉴定人肌肉细胞中钙诱导的坏死的调节剂。我们的屏幕确定了多个可以增强或抑制该过程的分子回路，包括溶酶体钙通道TPCN1，线粒体介体TOMM7，Ran结合蛋白RanBP9，组蛋白去乙酰化酶HDAC2，趋化因子CCL11和Arp2 / 3复杂调节子胶质成熟因子-γ（GMFG ）。值得注意的是，已鉴定出许多可药用酶，包括控制蛋白酶体胰凝乳蛋白酶样肽酶活性的蛋白酶体β5亚基（由PSMB5基因编码）。这些发现为发现药理学干预措施开辟了可能性，该药理学干预措施可以为以坏死细胞过多（或过少）为特征的无数疾病患者提供治疗益处，

更新日期：2019-09-16

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