Oxidative Processing of Latent Fas in the Endoplasmic Reticulum Controls the Strength of Apoptosis
Oxidative Processing of Latent Fas in the Endoplasmic Reticulum Controls the Strength of Apoptosis
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DOI：
10.1128/mcb.00125-12
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发表时间：
2012-09-01
影响因子：
5.3
通讯作者：
Janssen-Heininger, Yvonne M. W.
中科院分区：
文献类型：
--
作者：
Anathy, Vikas;Roberson, Elle;Janssen-Heininger, Yvonne M. W.
我们最近证明了死亡受体Fas的谷胱甘肽基化(Fas-SSG)放大了细胞的凋亡(V.Anathy等人，J.细胞生物学)。184：241-252,2009)。在目前的研究中，我们证明了细胞中存在不同的Fas池。表面Fas结扎后，内质网(ER)中一个单独的潜在Fas池经历了快速的氧化处理，其特征是游离巯基含量(Fas-SH)的丧失和导致Cys294的S谷胱甘肽基化增加，导致表面Fas的增加。在内质网中，FasL能迅速诱导Fas与ERp57和谷胱甘肽S转移酶pi的结合，ERp57和GSTp1分别是一种蛋白质二硫键异构酶和S谷胱甘肽转移酶的催化剂。阻断或抑制ERp57和GSTP1可显著减少FasL诱导的氧化过程和Fas的S谷胱甘肽基化，从而减少死亡诱导信号复合体的形成和caspase活性，提高存活率。博莱霉素诱导的肺纤维化伴随着Fas-ERp57-GSTP1和Fas的S-谷胱甘肽相互作用的增加。重要的是，在短干扰RNA介导的ERp57和GSTP消融后，纤维化在很大程度上得到了预防。总而言之，这些发现阐明了一种调控开关，即配体启动的潜伏Fas的氧化处理，它控制着细胞凋亡的强度。
We recently demonstrated that S-glutathionylation of the death receptor Fas (Fas-SSG) amplifies apoptosis (V. Anathy et al., J. Cell Biol. 184: 241-252, 2009). In the present study, we demonstrate that distinct pools of Fas exist in cells. Upon ligation of surface Fas, a separate pool of latent Fas in the endoplasmic reticulum (ER) underwent rapid oxidative processing characterized by the loss of free sulfhydryl content (Fas-SH) and resultant increases in S-glutathionylation of Cys294, leading to increases of surface Fas. Stimulation with FasL rapidly induced associations of Fas with ERp57 and glutathione S-transferase pi (GSTP), a protein disulfide isomerase and catalyst of S-glutathionylation, respectively, in the ER.Knockdown or inhibition of ERp57 and GSTP1 substantially decreased FasL-induced oxidative processing and S-glutathionylation of Fas, resulting in decreased death-inducing signaling complex formation and caspase activity and enhanced survival. Bleomycin-induced pulmonary fibrosis was accompanied by increased interactions between Fas-ERp57-GSTP1 and S-glutathionylation of Fas. Importantly, fibrosis was largely prevented following short interfering RNA-mediated ablation of ERp57 and GSTP. Collectively, these findings illuminate a regulatory switch, a ligand-initiated oxidative processing of latent Fas, that controls the strength of apoptosis.