UBASH3A Mediates Risk for Type 1 Diabetes Through Inhibition of T-Cell Receptor-Induced NF-κB Signaling
UBASH3A Mediates Risk for Type 1 Diabetes Through Inhibition of T-Cell Receptor-Induced NF-κB Signaling
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DOI：
10.2337/db16-1023
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发表时间：
2017-07-01
期刊：
影响因子：
7.7
通讯作者：
Concannon, Patrick
中科院分区：
文献类型：
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作者：
Ge, Yan;Paisie, Taylor K.;Concannon, Patrick
虽然已经在人类中绘制了超过40个1型糖尿病（T1 D）风险位点，但T1 D的致病基因和变体在很大程度上是未知的。在这里，我们研究了21q22.3风险位点中的候选基因-UBASH 3A，该基因主要在T细胞中表达，被认为在很大程度上起着冗余的作用。UBASH 3A中的遗传变异已被证明与除了T1 D之外的几种自身免疫性疾病相关。然而，这些遗传关联背后的分子机制尚未得到解决。我们的研究揭示了UBASH 3A在人T细胞中以前未被认识到的作用：UBASH 3A通过特异性抑制I κ B激酶复合物的活化来减弱T细胞受体（TCR）刺激后的NF-κ B信号转导。我们鉴定了UBASH 3A与非降解多聚泛素链、TAK 1和NEMO的新型相互作用，表明UBASH 3A通过泛素依赖性机制调节NF-κ B信号通路。最后，我们发现rs 11203203和rs 80054410（UBASH 3A中的两个T1 D相关变体）的风险等位基因在TCR刺激后增加人原代CD 4（+）T细胞中的UBASH 3A表达，通过其对I κ B激酶复合物的作用抑制NF-κ B信号传导，并导致IL 2基因表达减少。
Although over 40 type 1 diabetes (T1D) risk loci have been mapped in humans, the causative genes and variants for T1D are largely unknown. Here, we investigated a candidate gene in the 21q22.3 risk locus-UBASH3A, which is primarily expressed in T cells where it is thought to play a largely redundant role. Genetic variants in UBASH3A have been shown to be associated with several autoimmune diseases in addition to T1D. However, the molecular mechanism underlying these genetic associations is unresolved. Our study reveals a previously unrecognized role of UBASH3A in human T cells: UBASH3A attenuates the NF-kappa B signal transduction upon T-cell receptor (TCR) stimulation by specifically suppressing the activation of the I kappa B kinase complex. We identify novel interactions of UBASH3A with nondegradative polyubiquitin chains, TAK1 and NEMO, suggesting that UBASH3A regulates the NF-kappa B signaling pathway by an ubiquitin-dependent mechanism. Finally, we show that risk alleles at rs11203203 and rs80054410, two T1D-associated variants in UBASH3A, increase UBASH3A expression in human primary CD4(+) T cells upon TCR stimulation, inhibiting NF-kappa B signaling via its effects on the I kappa B kinase complex and resulting in reduced IL2 gene expression.