Dipartimento di Scienze e Tecnologie, Università degli Studi del Sannio, Benevento, Italy.
Genus Biotech, Università del Sannio, Benevento, Italy.
J Cell Physiol. 2020 Mar;235(3):1895-1902. doi: 10.1002/jcp.29161. Epub 2019 Sep 4.
CARD14/CARMA2sh (CARMA2sh) is a scaffold protein whose mutations are associated with the onset of human genetic psoriasis and other inflammatory skin disorders. Here we show that the immunomodulatory adapter protein TRAF family member-associated NF-κB activator (TANK) forms a complex with CARMA2sh and MALT1 in a human keratinocytic cell line. We also show that CARMA2 and TANK are individually required to activate the nuclear factor κB (NF-κB) response following exposure to polyinosinic-polycytidylic (poly [I:C]), an agonist of toll-like receptor 3. Finally, we present data indicating that TANK is essential for activation of the TBK1/IRF3 pathway following poly (I:C) stimulation, whereas CARMA2sh functions as a repressor of it. More important, we report that two CARMA2sh mutants associated with psoriasis bind less efficiently to TANK and are therefore less effective in suppressing the TBK1/IRF3 pathway. Overall, our data indicate that TANK and CARMA2sh regulate TLR3 signaling in human keratinocytes, which could play a role in the pathophysiology of psoriasis.
CARD14/CARMA2sh（CARMA2sh）是一种支架蛋白，其突变与人类遗传性银屑病和其他炎症性皮肤疾病的发病有关。在这里，我们表明，免疫调节接头蛋白 TRAF 家族成员相关 NF-κB 激活物（TANK）在人角质形成细胞系中与 CARMA2sh 和 MALT1 形成复合物。我们还表明，CARMA2 和 TANK 分别需要在暴露于多聚肌苷酸-多聚胞苷酸（poly [I：C]）后激活核因子 κB（NF-κB）反应，poly [I：C] 是 Toll 样受体 3 的激动剂。最后，我们提供的数据表明，TANK 对于 poly（I：C）刺激后 TBK1/IRF3 途径的激活是必不可少的，而 CARMA2sh 则作为其抑制剂发挥作用。更重要的是，我们报告了两种与银屑病相关的 CARMA2sh 突变体与 TANK 的结合效率较低，因此在抑制 TBK1/IRF3 途径方面的效果较差。总体而言，我们的数据表明 TANK 和 CARMA2sh 调节人类角质形成细胞中的 TLR3 信号转导，这可能在银屑病的病理生理学中起作用。
