Fas/CD95 prevents autoimmunity independently of lipid raft localization and efficient apoptosis induction.
Fas/CD95 prevents autoimmunity independently of lipid raft localization and efficient apoptosis induction.
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DOI：
10.1038/ncomms13895
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发表时间：
2016-12-23
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
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作者：
影响Fas/CD 95 TNF家族受体的凋亡诱导功能的突变导致自身免疫性和淋巴组织增生性疾病。然而，Fas也可以共刺激T细胞活化，促进肿瘤细胞的生长和转移。在膜近端半胱氨酸残基的棕榈酰化使Fas定位于脂筏微结构域并诱导细胞凋亡。在这里，我们表明，棕榈酰化缺陷的Fas C194 V突变体是有缺陷的诱导原代小鼠T细胞，B细胞和树突状细胞的凋亡，同时保留能力，以提高幼稚T细胞分化。尽管不能有效地诱导细胞死亡，Fas C194 V受体阻止Fas缺陷小鼠中发展的淋巴积聚和自身免疫。这些发现表明，通过Fas诱导的凋亡依赖于受体棕榈酰化在初级免疫细胞，Fas可能通过诱导凋亡以外的机制防止自身免疫。Fas驱动细胞凋亡，这种受体的突变可以通过细胞死亡的失败引起自身免疫。在这里，作者使用lpr/lpr小鼠与棕榈酰化缺陷突变Fas提供的证据表明，Fas可能会限制自发性自身免疫通过非凋亡机制。
Mutations affecting the apoptosis-inducing function of the Fas/CD95 TNF-family receptor result in autoimmune and lymphoproliferative disease. However, Fas can also costimulate T-cell activation and promote tumour cell growth and metastasis. Palmitoylation at a membrane proximal cysteine residue enables Fas to localize to lipid raft microdomains and induce apoptosis in cell lines. Here, we show that a palmitoylation-defective Fas C194V mutant is defective in inducing apoptosis in primary mouse T cells, B cells and dendritic cells, while retaining the ability to enhance naive T-cell differentiation. Despite inability to efficiently induce cell death, the Fas C194V receptor prevents the lymphoaccumulation and autoimmunity that develops in Fas-deficient mice. These findings indicate that induction of apoptosis through Fas is dependent on receptor palmitoylation in primary immune cells, and Fas may prevent autoimmunity by mechanisms other than inducing apoptosis. Fas drives apoptosis and mutations in this receptor can cause autoimmunity through failure of cell death. Here, the authors use lpr/lpr mice with palmitoylation-defective mutant Fas to provide evidence that Fas might limit spontaneous autoimmunity through a non-apoptotic mechanism.
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