Dual Role of Act1 in Keratinocyte Differentiation and Host Defense: TRAF3IP2 Silencing Alters Keratinocyte Differentiation and Inhibits IL-17 Responses.
Dual Role of Act1 in Keratinocyte Differentiation and Host Defense: TRAF3IP2 Silencing Alters Keratinocyte Differentiation and Inhibits IL-17 Responses.
复制标题
DOI：
10.1016/j.jid.2016.12.032
复制
发表时间：
2017-07
期刊：
影响因子：
--
通讯作者：
Elder JT
中科院分区：
文献类型：
--
作者：
Lambert S;Swindell WR;Tsoi LC;Stoll SW;Elder JT
TRAF3IP2是编码Act1的候选银屑病易感基因，Act1是一种具有泛素连接酶活性的接头蛋白，将IL-17受体连接到下游信号通路。我们利用四环素诱导的针对TRAF3IP2的shRNA研究了Act1在角质形成细胞对IL-17的反应中的作用。TET暴露7天有效地沉默了TRAF3IP2mRNA和Act1蛋白，导致761个基因的表达发生显著变化(495个下调，266个上调，1.5倍，p<；0.05)。基因本体论分析表明，受TRAF3IP2沉默影响的基因参与了表皮分化，早期分化基因(KRT1、KRT10、DSC1、DSG1)下调，晚期分化基因(SPRR2、SPRR3、LCE3)上调。AP1结合位点在TRAF3IP2沉默上调的基因上游丰富。相应地，在TRAF3IP2沉默的细胞中，FosB和Fra1的核表达增加。许多参与宿主防御的基因是由IL-17以依赖于TRAF3IP2的方式诱导的。炎症分化条件(融合后4天的血清添加)显著增强了这些IL-17反应，同时增加了基础水平和依赖于TRAF3IP2沉默的多个晚期分化基因的上调。这些发现表明，TRAF3IP2可能会改变表皮稳态和角质形成细胞防御反应，从而影响银屑病的风险。
TRAF3IP2 is a candidate psoriasis susceptibility gene encoding Act1, an adaptor protein with ubiquitin ligase activity that couples the IL-17 receptor to downstream signaling pathways. We investigated the role of Act1 in keratinocyte responses to IL-17 using a tetracycline inducible shRNA targeting TRAF3IP2. Tet exposure for seven days effectively silenced TRAF3IP2 mRNA and Act1 protein, resulting in 761 genes with significant changes in expression (495 down, 266 up, >1.5-fold, p<0.05). Gene Ontology analysis revealed that genes affected by TRAF3IP2 silencing are involved in epidermal differentiation, with early differentiation genes (KRT1, KRT10, DSC1, DSG1) being downregulated and late differentiation genes (SPRR2, SPRR3, LCE3) being upregulated. AP1 binding sites were enriched upstream of genes up-regulated by TRAF3IP2 silencing. Correspondingly, nuclear expression of FosB and Fra1 was increased in TRAF3IP2-silenced cells. Many genes involved in host defense were induced by IL-17 in a TRAF3IP2-dependent fashion. Inflammatory differentiation conditions (serum addition for 4 days postconfluence) markedly amplified these IL-17 responses, while increasing basal levels and TRAF3IP2 silencing-dependent upregulation of multiple late differentiation genes. These findings suggest that TRAF3IP2 may alter both epidermal homeostasis and keratinocyte defense responses to influence psoriasis risk.
登录
查看更多内容
影响因子：
4.4
作者：
Claudio, Estefania;Sonder, Soren Ulrik;Saret, Sun;Carvalho, Gabrielle;Ramalingam, Thirumalai R.;Wynn, Thomas A.;Chariot, Alain;Garcia-Perganeda, Antonio;Leonardi, Antonio;Paun, Andrea;Chen, Amy;Ren, Nina Y.;Wang, Hongshan;Siebenlist, Ulrich
通讯作者：
Siebenlist, Ulrich
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
3.6
作者：
Gutowska-Owsiak, Danuta;Schaupp, Anna L.;Ogg, Graham S.
通讯作者：
Ogg, Graham S.
影响因子：
3.7
作者：
Banno, Tomohiro;Blumenberg, Miroslav
通讯作者：
Blumenberg, Miroslav
影响因子：
6.5
作者：
GOTTLIEB, AB;GROSSMAN, RM;KRUEGER, JG
通讯作者：
KRUEGER, JG