A novel regulatory relationship between RIPK4 and ELF3 in keratinocytes
A novel regulatory relationship between RIPK4 and ELF3 in keratinocytes
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DOI：
10.1016/j.cellsig.2016.09.006
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发表时间：
2016-12-01
影响因子：
4.8
通讯作者：
Reynolds, Eric C.
中科院分区：
文献类型：
--
作者：
Scholz, Glen M.;Sulaiman, Nur S.;Reynolds, Eric C.
角质形成细胞是表面上皮细胞（如牙龈和表皮）屏障功能的中心。RIPK 4是角质形成细胞分化的关键调节因子;然而，其发挥作用的信号传导途径仍然不清楚。在这项研究中，我们确定了RIPK 4和ELF 3，ETS家族转录因子之间的调节关系。RIPK 4被证明是重要的上调ELF 3基因表达的PKC激动剂PMA在口腔和表皮角质形成细胞。RIPK 4部分通过磷酸化并由此激活IRF 6转录因子来促进角质形成细胞分化。值得注意的是，IRF 6的沉默抑制了PMA诱导的ELF 3的表达。GRHL 3转录因子（IRF 6的下游靶基因）在ELF 3表达调控中的作用也得到了类似的证实。ELF 3先前已显示调节SPPRIA和SPRRIB的表达，SPPRIA和SPRRIB是有助于角质形成细胞角化的富含脯氨酸的小蛋白。因此，RIPK 4和IRF 6在PMA诱导的SPRRIA和SPRRIB表达中起重要作用。它们对于TGM 1的上调也很重要，TGM 1是一种在角质形成细胞角化期间催化蛋白质（包括富含脯氨酸的小蛋白）交联的转氨酶。RIPK 4也显示独立于IRF 6上调TGM 2的表达。总的来说，我们的研究结果将RIPK 4定位在角质形成细胞中分层IRF 6-GRHL 3-ELF 3转录因子途径的上游，并提供了RIPK 4在角质形成细胞角化调节中的潜在作用的见解。(C)2016 Elsevier Inc. All rights reserved.
Keratinocytes are central to the barrier functions of surface epithelia, such as the gingiva and epidermis. RIPK4 is a key regulator of keratinocyte differentiation; however, the signalling pathways in which it functions remain poorly defined. In this study, we identified a regulatory relationship between RIPK4 and ELF3, an ETS family transcription factor. RIPK4 was shown to be important for the upregulation of ELF3 gene expression by the PKC agonist PMA in both oral and epidermal keratinocytes. RIPK4 promotes keratinocyte differentiation in part by phosphorylating and thereby activating the IRF6 transcription factor. Significantly, silencing of IRF6 inhibited the PMA-inducible expression of ELF3. A role for the GRHL3 transcription factor, a downstream target gene of IRF6, in the regulation of ELF3 expression was similarly demonstrated. ELF3 has previously been shown to regulate the expression of SPPRIA and SPRRIB, small proline-rich proteins that contribute to the cornification of keratinocytes. Consistently, RIPK4 and IRF6 were important for the PMA-inducible expression of SPRRIA and SPRRIB. They were also important for the upregulation of TGM1, a transglutaminase that catalyses the cross linking of proteins, including small proline-rich proteins, during keratinocyte cornification. RIPK4 was also shown to upregulate the expression of TGM2 independently of IRF6. Collectively, our findings position RIPK4 upstream of a hierarchal IRF6-GRHL3-ELF3 transcription factor pathway in keratinocytes, as well as provide insight into a potential role for RIPK4 in the regulation of keratinocyte cornification. (C) 2016 Elsevier Inc. All rights reserved.