Activation of STING requires palmitoylation at the Golgi.
Activation of STING requires palmitoylation at the Golgi.
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DOI：
10.1038/ncomms11932
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发表时间：
2016-06-21
影响因子：
16.6
通讯作者：
Taguchi T
中科院分区：
文献类型：
--
作者：
Mukai K;Konno H;Akiba T;Uemura T;Waguri S;Kobayashi T;Barber GN;Arai H;Taguchi T
干扰素基因刺激因子（STING）是I型干扰素对DNA病原体的应答所必需的。响应于DNA和/或环状二核苷酸的存在，STING从内质网易位到核周区室。然而，这种亚细胞易位的作用仍然不清楚。在这里，我们表明，棕榈酰化的STING在高尔基体是必不可少的激活STING。用棕榈酰化抑制剂2-溴棕榈酸酯（2-BP）治疗抑制STING的棕榈酰化并消除I型干扰素应答。两个膜近端Cys残基（Cys 88/91）的突变抑制棕榈酰化，这种STING突变体不能诱导STING依赖的宿主防御基因。在自身免疫性疾病患者中发现了组成型诱导I型干扰素应答的STING变体。由这些STING变体引起的应答被2-BP或Cys 88/91 Ser突变的引入有效地抑制。我们的研究结果可能会导致新的治疗细胞溶质DNA触发的自身炎症性疾病。 STING对于针对外源DNA的I型干扰素免疫反应至关重要。在这里，作者表明，在高尔基体上的STING棕榈酰化是激活下游信号传导所必需的，并且某些STING变体的高尔基体定位增加可能在某些情况下导致自身免疫性疾病。
Stimulator of interferon genes (STING) is essential for the type I interferon response against DNA pathogens. In response to the presence of DNA and/or cyclic dinucleotides, STING translocates from the endoplasmic reticulum to perinuclear compartments. However, the role of this subcellular translocation remains poorly defined. Here we show that palmitoylation of STING at the Golgi is essential for activation of STING. Treatment with palmitoylation inhibitor 2-bromopalmitate (2-BP) suppresses palmitoylation of STING and abolishes the type I interferon response. Mutation of two membrane-proximal Cys residues (Cys88/91) suppresses palmitoylation, and this STING mutant cannot induce STING-dependent host defense genes. STING variants that constitutively induce the type I interferon response were found in patients with autoimmune diseases. The response elicited by these STING variants is effectively inhibited by 2-BP or an introduction of Cys88/91Ser mutation. Our results may lead to new treatments for cytosolic DNA-triggered autoinflammatory diseases. STING is essential for the type I interferon immune response to foreign DNA. Here, the authors show that palmitoylation of STING at the Golgi is required for activating downstream signalling, and increased Golgi localization of certain STING variants may cause autoimmune disease in some cases.