Molnár Tamás, Pallagi Petra, Tél Bálint, Király Róbert, Csoma Eszter, Jenei Viktória, Varga Zsófia, Gogolák Péter, Odile Hueber Anne, Máté Zoltán, Erdélyi Ferenc, Szabó Gábor, Pettkó-Szandtner Aladár, Bácsi Attila, Virág László, Maléth József, Koncz Gábor
Department of Immunology, Faculty of Medicine, University of Debrecen, Hungary.
Doctoral School of Molecular Cellular and Immune Biology, University of Debrecen, Hungary.
FEBS J. 2021 Nov;288(22):6476-6491. doi: 10.1111/febs.15898. Epub 2021 May 8.
Necroptosis is a regulated necrotic-like cell death modality which has come into the focus of attention since it is known to contribute to the pathogenesis of many inflammatory and degenerative diseases as well as to tumor regulation. Based on current data, necroptosis serves as a backup mechanism when death receptor-induced apoptosis is inhibited or absent. However, the necroptotic role of the proteins involved in mitochondrial apoptosis has not been investigated. Here, we demonstrated that the stimulation of several death and pattern recognition receptors induced necroptosis under caspase-compromised conditions in wild-type, but not in caspase-9-negative human Jurkat and murine MEF cells. Cerulein-induced pancreatitis was significantly reduced in mice with acinar cell-restricted caspase-9 gene knockout. The absence of caspase-9 led to impaired association of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and RIPK3 and resulted in decreased phosphorylation of RIP kinases, but the overexpression of RIPK1 or RIPK3 rescued the effect of caspase-9 deficiency. Inhibition of either Aurora kinase A (AURKA) or its known substrate, glycogen synthase kinase 3β (GSK3ß) restored necroptosis sensitivity of caspase-9-deficient cells, indicating an interplay between caspase-9 and AURKA-mediated pathways to regulate necroptosis. Our findings suggest that caspase-9 acts as a newly identified regulator of necroptosis, and thus, caspase-9 provides a promising therapeutic target to manipulate the immunological outcome of cell death.
坏死性凋亡是一种受调控的类坏死细胞死亡方式，自其被发现与多种炎症性和退行性疾病的发病机制以及肿瘤调控有关以来，已成为关注焦点。基于目前的数据，当死亡受体诱导的凋亡被抑制或不存在时，坏死性凋亡作为一种备用机制发挥作用。然而，参与线粒体凋亡的蛋白质的坏死性凋亡作用尚未得到研究。在此，我们证明在野生型细胞中，在半胱天冬酶功能受损的条件下，几种死亡和模式识别受体的刺激可诱导坏死性凋亡，但在半胱天冬酶-9阴性的人 Jurkat 细胞和小鼠 MEF 细胞中则不然。在腺泡细胞特异性半胱天冬酶-9基因敲除的小鼠中，雨蛙肽诱导的胰腺炎明显减轻。半胱天冬酶-9的缺失导致受体相互作用丝氨酸/苏氨酸蛋白激酶1（RIPK1）和RIPK3的结合受损，并导致RIP激酶的磷酸化减少，但RIPK1或RIPK3的过表达挽救了半胱天冬酶-9缺乏的影响。抑制极光激酶A（AURKA）或其已知底物糖原合酶激酶3β（GSK3β）可恢复半胱天冬酶-9缺陷细胞的坏死性凋亡敏感性，表明半胱天冬酶-9与AURKA介导的途径之间存在相互作用以调节坏死性凋亡。我们的研究结果表明，半胱天冬酶-9作为一种新发现的坏死性凋亡调节因子，因此，半胱天冬酶-9为操纵细胞死亡的免疫结果提供了一个有前景的治疗靶点。
