Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1.
Innate immunity pathways regulate the nephropathy gene Apolipoprotein L1.
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先天免疫途径调节肾病基因载脂蛋白L1。
DOI：
10.1038/ki.2014.270
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发表时间：
2015-02
影响因子：
19.6
通讯作者：
中科院分区：
文献类型：
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作者：
载脂蛋白L1(APOL1)风险变异极大地增加了非裔美国人患肾脏疾病的风险。在这里，我们报告了一组患者，他们在接受干扰素治疗时发展为塌陷性局灶节段性肾小球硬化，所有患者都携带APOL1高危基因。这一发现提高了干扰素和刺激干扰素产生的分子模式识别受体可能导致APOL1相关肾脏疾病的可能性。在细胞培养中，干扰素和Toll样受体激动剂使APOL1的表达增加200倍，在某些情况下，在基础条件下检测不到转录本的出现。PolyI：C是一种双链RNA TLR3激动剂，通过直接上调干扰素或通过干扰素非依赖、IRF-3依赖的途径增加APOL1的表达。利用药物抑制剂、shRNA敲除和染色质免疫沉淀，我们发现非干扰素依赖的TLR3途径依赖于通过TBK1、NF-kB和JAK激酶的信号以及APOL1转录起始点上IRF1、IRF2和STAT2的结合。我们还证明过表达APOL1风险变异体比过表达野生型APOL1蛋白对细胞的伤害更大。我们的研究表明，抗病毒途径可能是APOL1高危基因个体肾脏疾病的重要诱因，并确定了预防或治疗的潜在靶点。
Apolipoprotein L1 (APOL1) risk variants greatly elevate the risk of kidney disease in African Americans. Here we report a cohort of patients who developed collapsing focal segmental glomerulosclerosis while receiving therapeutic interferon, all of whom carried the APOL1 high-risk genotype. This finding raised the possibility that interferons and the molecular pattern recognition receptors that stimulate interferon production may contribute to APOL1-associated kidney disease. In cell culture, interferons and toll-like receptor agonists increased APOL1 expression by up to 200-fold, in some cases with the appearance of transcripts not detected under basal conditions. PolyI:C, a double-stranded RNA TLR3 agonist, increased APOL1 expression by upregulating interferons directly or through an interferon-independent, IRF-3 dependent pathway. Using pharmacological inhibitors, shRNA knockdown, and chromatin immunoprecipitation, we found that the interferon-independent TLR3 pathway relied on signaling through TBK1, NF-kB, and Jak kinases, and on binding of IRF1, IRF2, and STAT2 at the APOL1 transcription start site. We also demonstrate that overexpression of the APOL1 risk variants is more injurious to cells than overexpression of the wild-type APOL1 protein. Our study illustrates that anti-viral pathways may be an important inducer of kidney disease in individuals with the APOL1 high-risk genotype and identifies potential targets for prevention or treatment.
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DOI：
10.1126/science.1193032
发表时间：
2010-08-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Genovese G;Friedman DJ;Ross MD;Lecordier L;Uzureau P;Freedman BI;Bowden DW;Langefeld CD;Oleksyk TK;Uscinski Knob AL;Bernhardy AJ;Hicks PJ;Nelson GW;Vanhollebeke B;Winkler CA;Kopp JB;Pays E;Pollak MR
通讯作者：
Pollak MR
影响因子：
13.6
作者：
Kopp, Jeffrey B.;Nelson, George W.;Winkler, Cheryl A.
通讯作者：
Winkler, Cheryl A.
影响因子：
64.5
作者：
Dixit E;Boulant S;Zhang Y;Lee AS;Odendall C;Shum B;Hacohen N;Chen ZJ;Whelan SP;Fransen M;Nibert ML;Superti-Furga G;Kagan JC
通讯作者：
Kagan JC
影响因子：
13.6
作者：
Albaqumi, Mamdouh;Soos, Timothy J.;Nelson, Peter J.
通讯作者：
Nelson, Peter J.
影响因子：
4.4
作者：
Monajemi, H;Fontijn, RD;Horrevoets, AJG
通讯作者：
Horrevoets, AJG