STING signalling is terminated through ESCRT-dependent microautophagy of vesicles originating from recycling endosomes.
STING signalling is terminated through ESCRT-dependent microautophagy of vesicles originating from recycling endosomes.
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STING信号传导通过源自再循环内体的囊泡的ESCRT依赖性微自噬终止。
DOI：
10.1038/s41556-023-01098-9
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发表时间：
2023-03
影响因子：
21.3
通讯作者：
Taguchi, Tomohiko
中科院分区：
文献类型：
--
作者：
Kuchitsu, Yoshihiko;Mukai, Kojiro;Uematsu, Rei;Takaada, Yuki;Shinojima, Ayumi;Shindo, Ruri;Shoji, Tsumugi;Hamano, Shiori;Ogawa, Emari;Sato, Ryota;Miyake, Kensuke;Kato, Akihisa;Kawaguchi, Yasushi;Nishitani-Isa, Masahiko;Izawa, Kazushi;Nishikomori, Ryuta;Yasumi, Takahiro;Suzuki, Takehiro;Dohmae, Naoshi;Uemura, Takefumi;Barber, Glen N. N.;Arai, Hiroyuki;Waguri, Satoshi;Taguchi, Tomohiko
干扰素基因刺激因子（STING）对于针对多种DNA病原体的I型干扰素反应至关重要。在细胞质DNA出现时，STING从内质网转移到高尔基体，在高尔基体中STING激活下游激酶TBK1，然后通过循环内体（REs）转移到溶酶体进行降解。尽管STING激活的分子机制已被广泛研究和明确，但STING降解和失活的潜在机制尚未完全阐明。在此我们表明，STING是通过运输所需的内体分选复合物（ESCRT）驱动的微自噬而降解的。Airyscan超分辨率显微镜和相关光/电子显微镜显示，源自循环内体的STING阳性囊泡直接被包裹进Lamp1阳性区室。对哺乳动物Vps基因（其酵母同源物调节高尔基体到液泡的运输）的筛选表明，ESCRT蛋白对于STING包裹进Lamp1阳性区室是必不可少的。敲低ESCRT的组成成分Tsg101和Vps4会导致STING囊泡在细胞质中积累，从而导致I型干扰素反应持续。在人原代T细胞中敲低Tsg101会导致干扰素刺激基因的表达增加。STING在通过高尔基体/循环内体的过程中，其赖氨酸288位点会发生K63连接的泛素化，并且这种泛素化对于STING的降解是必需的。我们的结果揭示了一种防止先天免疫信号过度激活的分子机制，该机制在循环内体中起作用。
Kuchitsu等人表明，源自循环内体的STING阳性囊泡在STING泛素化之后被包裹进溶酶体，并且这个过程需要ESCRT蛋白Tsg101和Vps4。
Stimulator of interferon genes (STING) is essential for the type I interferon response against a variety of DNA pathogens. Upon emergence of cytosolic DNA, STING translocates from the endoplasmic reticulum to the Golgi where STING activates the downstream kinase TBK1, then to lysosome through recycling endosomes (REs) for its degradation. Although the molecular machinery of STING activation is extensively studied and defined, the one underlying STING degradation and inactivation has not yet been fully elucidated. Here we show that STING is degraded by the endosomal sorting complexes required for transport (ESCRT)-driven microautophagy. Airyscan super-resolution microscopy and correlative light/electron microscopy suggest that STING-positive vesicles of an RE origin are directly encapsulated into Lamp1-positive compartments. Screening of mammalian Vps genes, the yeast homologues of which regulate Golgi-to-vacuole transport, shows that ESCRT proteins are essential for the STING encapsulation into Lamp1-positive compartments. Knockdown of Tsg101 and Vps4, components of ESCRT, results in the accumulation of STING vesicles in the cytosol, leading to the sustained type I interferon response. Knockdown of Tsg101 in human primary T cells leads to an increase the expression of interferon-stimulated genes. STING undergoes K63-linked ubiquitination at lysine 288 during its transit through the Golgi/REs, and this ubiquitination is required for STING degradation. Our results reveal a molecular mechanism that prevents hyperactivation of innate immune signalling, which operates at REs. Kuchitsu et al. show that STING-positive vesicles of a recycling endosome origin are encapsulated into lysosomes after STING ubiquitination and this process requires ESCRT proteins Tsg101 and Vps4.
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影响因子：
21.3
作者：
通讯作者：
--
DOI：
10.1038/nri3921
发表时间：
2015-12
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.9
作者：
Akbari, Soheil;Sevinc, Gulben Gurhan;Erdal, Esra
通讯作者：
Erdal, Esra
糖蛋白2是人类胰腺祖细胞的特定细胞表面标记。
影响因子：
16.6
作者：
Cogger KF;Sinha A;Sarangi F;McGaugh EC;Saunders D;Dorrell C;Mejia-Guerrero S;Aghazadeh Y;Rourke JL;Screaton RA;Grompe M;Streeter PR;Powers AC;Brissova M;Kislinger T;Nostro MC
通讯作者：
Nostro MC
影响因子：
8.8
作者：
Ang LT;Tan AKY;Autio MI;Goh SH;Choo SH;Lee KL;Tan J;Pan B;Lee JJH;Lum JJ;Lim CYY;Yeo IKX;Wong CJY;Liu M;Oh JLL;Chia CPL;Loh CH;Chen A;Chen Q;Weissman IL;Loh KM;Lim B
通讯作者：
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