Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Intramural Research Program, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
Center for Cell Engineering and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Nat Commun. 2016 Dec 23;7:13895. doi: 10.1038/ncomms13895.
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.
影响 Fas/CD95 TNF 家族受体凋亡诱导功能的突变可导致自身免疫和淋巴组织增生性疾病。然而，Fas 也可以共刺激 T 细胞的活化，并促进肿瘤细胞的生长和转移。在膜近端半胱氨酸残基上的棕榈酰化使 Fas 能够定位于脂筏微区，并在细胞系中诱导细胞凋亡。在这里，我们发现棕榈酰化缺陷的 Fas C194V 突变体在诱导原代小鼠 T 细胞、B 细胞和树突状细胞凋亡方面存在缺陷，而增强初始 T 细胞分化的能力得以保留。尽管不能有效地诱导细胞死亡，但 Fas C194V 受体可防止 Fas 缺陷型小鼠中发生的淋巴积聚和自身免疫。这些发现表明，在原代免疫细胞中通过 Fas 诱导细胞凋亡依赖于受体的棕榈酰化，而 Fas 可能通过诱导细胞凋亡以外的机制来防止自身免疫。
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