Nucleosomal dsDNA Stimulates APOL1 Expression in Human Cultured Podocytes by Activating the cGAS/IF116-STING Signaling Pathway
Nucleosomal dsDNA Stimulates APOL1 Expression in Human Cultured Podocytes by Activating the cGAS/IF116-STING Signaling Pathway
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DOI：
10.1038/s41598-019-51998-w
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发表时间：
2019-10-29
影响因子：
4.6
通讯作者：
Popik, Waldemar
中科院分区：
文献类型：
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作者：
Davis, Shamara E.;Khatua, Atanu K.;Popik, Waldemar
APOL 1等位基因G1和G2与非裔美国人更快进展为狼疮性肾炎（LN）相关终末期肾病（LN-ESRD）相关I型干扰素（IFN）和核小体相关双链DNA（dsDNA）片段（nsDNA）水平的增加是这种疾病的标志。在这里，我们确定环GMP-AMP合酶（CGAS）和干扰素诱导蛋白16（IFI 16）作为人类永生化足细胞中的主要DNA传感器。我们还表明，nsDNA通过cGAS/IFI 16-STING途径通过IRF 3激活触发APOL 1和IFN β的表达。我们证明，最大的APOL 1表达也需要激活I型IFN受体（IFNAR）和STAT 1信号由响应nsDNA产生的IFN β或外源性IFN β触发。最后，我们发现STAT 1的激活足以上调IFI 16，随后通过正反馈机制促进APOL 1的表达。总的来说，我们发现nsDNA诱导的APOL 1表达是由cGAS/IFI 16-STING通路激活触发的IFN β非依赖性和依赖性信号通路介导的。我们提出，同时抑制STING和IFNAR-STAT 1通路可能会减弱IFI 16表达，减少IFI 16-cGAS串扰，并防止人类足细胞中响应nsDNA的APOL 1过度表达。
APOL1 alleles G1 and G2 are associated with faster progression to lupus nephritis (LN)-associated end-stage renal disease (LN-ESRD) in African Americans. Increased levels of type I interferons (IFNs) and nucleosome-associated double-stranded DNA (dsDNA) fragments (nsDNA) are the hallmark of this disease. Here, we identify cyclic GMP-AMP synthase (cGAS) and interferon-inducible protein 16 (IFI16) as the major DNA sensors in human immortalized podocytes. We also show that nsDNA triggers the expression of APOL1 and IFN beta via IRF3 activation through the cGAS/IFI16-STING pathway. We demonstrate that maximal APOL1 expression also requires the activation of type I IFN receptor (IFNAR) and STAT1 signaling triggered by IFN beta produced in response to nsDNA, or by exogenous IFN beta . Finally, we show that STAT1 activation is sufficient to upregulate IFI16, subsequently boosting APOL1 expression through a positive feedback mechanism. Collectively, we find that nsDNA-induced APOL1 expression is mediated by both IFN beta-independent and dependent signaling pathways triggered by activation of the cGAS/IFI16-STING pathway. We propose that simultaneous inhibition of STING and the IFNAR-STAT1 pathway may attenuate IFI16 expression, reduce IFI16-cGAS cross-talk, and prevent excessive APOL1 expression in human podocytes in response to nsDNA.