小柯机器人

网格蛋白相关的AP-1控制STING信号的终止
2022-10-23 14:05

瑞士洛桑联邦理工学院Andrea Ablasser团队近期取得重要工作进展,他们研究发现网格蛋白相关的AP-1控制STING信号的终止。相关论文于2022年10月19日在线发表于《自然》杂志上。

研究人员发现适配器蛋白复合物1 (AP-1)调控STING依赖性免疫激活的终止。AP-1将磷酸化的STING筛选成网格蛋白包裹的转运囊泡,并运送到溶酶体内降解。研究人员在STING细胞膜C端尾巴(CTT)上发现了一个高度保守的二亮氨酸基序,它与TBK1依赖的CTT磷酸化一起决定了STING的AP-1接合。AP-1与磷酸化STING复合物形成的低温电子显微镜结构解释了TBK1激活的STING识别能力增强。对AP-1的抑制会加剧STING诱导的免疫反应。研究结果揭示STING负调控的结构机制,为了使免疫力得到短暂的激活,信号的启动与终止是密不可分的。

据介绍,干扰素基因的刺激器(STING)在环状GMP-AMP合成酶下游发挥DNA感应功能,或作为细菌环状二核苷酸和小分子的直接受体,在感染、癌症和免疫治疗期间激活免疫力。STING的精确调控对于确保免疫应答的平衡和防止有害的自身炎症是至关重要的。STING是一种跨膜蛋白,被激活后从内质网转运到高尔基体,并被蛋白激酶TBK1磷酸化,从而实现信号转导。STING信号在高尔基体结束的机制仍然未知。

附:英文原文

Title: Clathrin-associated AP-1 controls termination of STING signalling

Author: Liu, Ying, Xu, Pengbiao, Rivara, Sophie, Liu, Chong, Ricci, Jonathan, Ren, Xuefeng, Hurley, James H., Ablasser, Andrea

Issue&Volume: 2022-10-19

Abstract: Stimulator of interferon genes (STING) functions downstream of cyclic GMP-AMP synthase in DNA sensing or as a direct receptor for bacterial cyclic dinucleotides and small molecules to activate immunity during infection, cancer and immunotherapy1,2,3,4,5,6,7,8,9,10. Precise regulation of STING is essential to ensure balanced immune responses and prevent detrimental autoinflammation11,12,13,14,15,16. After activation, STING, a transmembrane protein, traffics from the endoplasmic reticulum to the Golgi, where its phosphorylation by the protein kinase TBK1 enables signal transduction17,18,19,20. The mechanism that ends STING signalling at the Golgi remains unknown. Here we show that adaptor protein complex 1 (AP-1) controls the termination of STING-dependent immune activation. We find that AP-1 sorts phosphorylated STING into clathrin-coated transport vesicles for delivery to the endolysosomal system, where STING is degraded21. We identify a highly conserved dileucine motif in the cytosolic C-terminal tail (CTT) of STING that, together with TBK1-dependent CTT phosphorylation, dictates the AP-1 engagement of STING. A cryo-electron microscopy structure of AP-1 in complex with phosphorylated STING explains the enhanced recognition of TBK1-activated STING. We show that suppression of AP-1 exacerbates STING-induced immune responses. Our results reveal a structural mechanism of negative regulation of STING and establish that the initiation of signalling is inextricably associated with its termination to enable transient activation of immunity.

DOI: 10.1038/s41586-022-05354-0

Source: https://www.nature.com/articles/s41586-022-05354-0

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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