Frederick Kenneth, Patel Rekha C
Department of Biological Sciences, University of South Carolina, Columbia, SC, United States.
Front Pharmacol. 2023 Feb 15;14:1118725. doi: 10.3389/fphar.2023.1118725. eCollection 2023.
DYT- is a movement disorder caused by mutations in the gene, which encodes for PACT, the protein activator of interferon-induced, double-stranded RNA (dsRNA)-activated protein kinase PKR. PACT brings about PKR's catalytic activation by a direct binding in response to stress signals and activated PKR phosphorylates the translation initiation factor eIF2α. Phosphorylation of eIF2α is the central regulatory event that is part of the integrated stress response (ISR), an evolutionarily conserved intracellular signaling network essential for adapting to environmental stresses to maintain healthy cells. A dysregulation of either the level or the duration of eIF2α phosphorylation in response to stress signals causes the normally pro-survival ISR to become pro-apoptotic. Our research has established that the mutations reported to cause DYT- lead to enhanced PACT-PKR interactions causing a dysregulation of ISR and an increased sensitivity to apoptosis. We have previously identified luteolin, a plant flavonoid, as an inhibitor of the PACT-PKR interaction using high-throughput screening of chemical libraries. Our results presented in this study indicate that luteolin is markedly effective in disrupting the pathological PACT-PKR interactions to protect DYT- cells against apoptosis, thus suggesting a therapeutic option for using luteolin to treat DYT- and possibly other diseases resulting from enhanced PACT-PKR interactions.
DYT-是一种由该基因突变引起的运动障碍，该基因编码PACT，即干扰素诱导的双链RNA（dsRNA）激活蛋白激酶PKR的蛋白激活剂。PACT通过响应应激信号直接结合实现PKR的催化激活，而激活的PKR使翻译起始因子eIF2α磷酸化。eIF2α的磷酸化是综合应激反应（ISR）的核心调节事件，ISR是一个进化上保守的细胞内信号网络，对适应环境应激以维持细胞健康至关重要。应激信号响应中eIF2α磷酸化水平或持续时间的失调会导致正常情况下具有促生存作用的ISR转变为促凋亡状态。我们的研究已经证实，据报道导致DYT-的这些突变会增强PACT-PKR相互作用，导致ISR失调并增加对凋亡的敏感性。我们之前通过对化学文库进行高通量筛选，已鉴定出植物黄酮类化合物木犀草素是PACT-PKR相互作用的抑制剂。我们在本研究中展示的结果表明，木犀草素在破坏病理性PACT-PKR相互作用以保护DYT-细胞免受凋亡方面具有显著效果，从而提示木犀草素可作为治疗DYT-以及可能由增强的PACT-PKR相互作用导致的其他疾病的一种治疗选择。
