Transcription-independent regulation of STING activation and innate immune responses by IRF8 in monocytes.
Transcription-independent regulation of STING activation and innate immune responses by IRF8 in monocytes.
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单核细胞中 IRF8 对 STING 激活和先天免疫反应的转录独立调节
DOI：
10.1038/s41467-022-32401-1
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发表时间：
2022-08-16
影响因子：
16.6
通讯作者：
Wang, Yan-Yi
中科院分区：
文献类型：
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作者：
Luo, Wei-Wei;Tong, Zhen;Cao, Pan;Wang, Fu-Bing;Liu, Ying;Zheng, Zhou-Qin;Wang, Su-Yun;Li, Shu;Wang, Yan-Yi
通过cGAS感测微生物或细胞/线粒体来源的胞质DNA经由衔接蛋白STING引发先天免疫应答。STING的活性如何在产生性先天免疫应答和诱导自身免疫之间平衡仍未解决。在这里，我们表明，干扰素调节因子8（IRF 8）是必不可少的有效激活STING介导的先天性免疫反应的单核细胞。IRF 8的这种功能不依赖于其在单核细胞分化中的转录作用。在未感染的细胞中，IRF 8通过其N-和C-末端尾部隔离其IRF相关结构域而保持无活性，这减少了其与STING的关联。在触发DNA传感途径后，IRF 8在丝氨酸151处磷酸化以允许其通过IRF相关结构域与STING缔合。这对于STING聚合和TBK 1介导的STING和IRF 3磷酸化至关重要。因此，IRF 8缺陷损害宿主对DNA病毒HSV-1的防御，并阻断DNA损伤诱导的细胞衰老。由于Trex 1缺乏而具有自身免疫表型的骨髓来源的单核细胞对IRF-8缺失产生应答，促炎细胞因子产生减少。来自系统性红斑狼疮患者的外周血单核细胞的特征在于在相同的丝氨酸残基处IRF 8的磷酸化升高，我们发现这在STING活化中是重要的，并且在这些细胞中STING是超活性的。总之，我们在此描述的IRF 8的转录非依赖性功能似乎介导STING活化，并且代表单核细胞中cGAS/STING先天免疫途径中的重要调节步骤。转录因子IRF 8已显示通过其DNA结合活性调节单核细胞分化。在这里，作者表明IRF 8还通过其与衔接蛋白STING的磷酸化依赖性缔合参与细胞溶质DNA传感，因此代表了单核细胞中免疫应答和自身免疫之间的重要检查点。
Sensing of cytosolic DNA of microbial or cellular/mitochondrial origin by cGAS initiates innate immune responses via the adaptor protein STING. It remains unresolved how the activity of STING is balanced between a productive innate immune response and induction of autoimmunity. Here we show that interferon regulatory factor 8 (IRF8) is essential for efficient activation of STING-mediated innate immune responses in monocytes. This function of IRF8 is independent of its transcriptional role in monocyte differentiation. In uninfected cells, IRF8 remains inactive via sequestration of its IRF-associated domain by its N- and C-terminal tails, which reduces its association with STING. Upon triggering the DNA sensing pathway, IRF8 is phosphorylated at Serine 151 to allow its association with STING via the IRF-associated domain. This is essential for STING polymerization and TBK1-mediated STING and IRF3 phosphorylation. Consistently, IRF8-deficiency impairs host defense against the DNA virus HSV-1, and blocks DNA damage-induced cellular senescence. Bone marrow-derived mononuclear cells which have an autoimmune phenotype due to deficiency of Trex1, respond to IRF-8 deletion with reduced pro-inflammatory cytokine production. Peripheral blood mononuclear cells from systemic lupus erythematosus patients are characterized by elevated phosphorylation of IRF8 at the same Serine residue we find to be important in STING activation, and in these cells STING is hyper-active. Taken together, the transcription-independent function of IRF8 we describe here appears to mediate STING activation and represents an important regulatory step in the cGAS/STING innate immune pathway in monocytes. The transcription factor IRF8 has been shown to regulate monocyte differentiation via its DNA-binding activity. Here authors show that IRF8 is also involved in cytosolic DNA sensing via its phosphorylation-dependent association to the adaptor protein STING, thus representing an important checkpoint between immune response and autoimmunity in monocytes.
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影响因子：
64.5
作者：
Karki R;Lee E;Place D;Samir P;Mavuluri J;Sharma BR;Balakrishnan A;Malireddi RKS;Geiger R;Zhu Q;Neale G;Kanneganti TD
通讯作者：
Kanneganti TD
IRF3和I型干扰物为心肌梗死提供了致命的反应。
影响因子：
82.9
作者：
King KR;Aguirre AD;Ye YX;Sun Y;Roh JD;Ng RP Jr;Kohler RH;Arlauckas SP;Iwamoto Y;Savol A;Sadreyev RI;Kelly M;Fitzgibbons TP;Fitzgerald KA;Mitchison T;Libby P;Nahrendorf M;Weissleder R
通讯作者：
Weissleder R
DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J
影响因子：
2.3
作者：
Kanno, Y;Levi, BZ;Ozato, K
通讯作者：
Ozato, K
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：
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