Sumoylation coordinates the repression of inflammatory and anti-viral gene-expression programs during innate sensing
Sumoylation coordinates the repression of inflammatory and anti-viral gene-expression programs during innate sensing
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DOI：
10.1038/ni.3342
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发表时间：
2016-02-01
影响因子：
30.5
通讯作者：
Dejean, Anne
中科院分区：
文献类型：
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作者：
Decque, Adrien;Joffre, Olivier;Dejean, Anne
病原体的先天感知会引发需要严格控制的炎性细胞因子反应。我们在这里发现，当Toll样受体(TLRs)与髓系细胞结合后，缺陷的总甲基化导致依赖于转录因子NF-kappa B的炎性细胞因子的分泌增加，并产生大量的I型干扰素信号。在小鼠中，降低总甲基化可增加对内毒素休克的易感性和对病毒感染的抵抗力。几种依赖于核因子-kappaB的炎性细胞因子的过度产生需要I型干扰素受体的表达，该受体确定I型干扰素是炎症的中心苏莫化控制的枢纽。从机制上讲，小的泛素样修饰物SUMO通过编码干扰素-β基因(Ifnb1)的末端增强子来抑制Ifnb1启动子的基础活性和刺激诱导的活性。因此，苏莫化通过沉默IfNB1的表达和严格抑制I型干扰素对TLR诱导的炎性细胞因子的产生的意外启动来抑制炎症。
Innate sensing of pathogens initiates inflammatory cytokine responses that need to be tightly controlled. We found here that after engagement of Toll-like receptors (TLRs) in myeloid cells, deficient sumoylation caused increased secretion of transcription factor NF-kappa B-dependent inflammatory cytokines and a massive type I interferon signature. In mice, diminished sumoylation conferred susceptibility to endotoxin shock and resistance to viral infection. Overproduction of several NF-kappa B-dependent inflammatory cytokines required expression of the type I interferon receptor, which identified type I interferon as a central sumoylation-controlled hub for inflammation. Mechanistically, the small ubiquitin-like modifier SUMO operated from a distal enhancer of the gene encoding interferon-beta (Ifnb1) to silence both basal and stimulus-induced activity of the Ifnb1 promoter. Therefore, sumoylation restrained inflammation by silencing Ifnb1 expression and by strictly suppressing an unanticipated priming by type I interferons of the TLR-induced production of inflammatory cytokines.