iRHOM2-dependent regulation of ADAM17 in cutaneous disease and epidermal barrier function
iRHOM2-dependent regulation of ADAM17 in cutaneous disease and epidermal barrier function
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DOI：
10.1093/hmg/ddu120
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发表时间：
2014-08-01
影响因子：
3.5
通讯作者：
Kelsell, David P.
中科院分区：
文献类型：
--
作者：
Brooke, Matthew A.;Etheridge, Sarah L.;Kelsell, David P.
iRHOM2是Rhomboid家族的高度保守的无催化活性的成员，其最近已显示调节巨噬细胞中多底物胞外域脱落酶ADAM 17（TACE）的成熟。显性iRHOM2突变是遗传性皮肤和食管癌易感综合征伴食管癌（TOC）的原因，表明该蛋白在上皮细胞中的作用。在这里，使用来自TOC患者的组织，我们证明了iRHOM2中TOC相关的突变导致表皮角质形成细胞中ADAM 17的成熟和活性增加，导致ADAM 17底物（包括EGF家族生长因子和促炎细胞因子）的脱落显著上调。这种活性伴随着增加的EGFR活性、增加的桥粒加工和不成熟的表皮桥粒的存在、上调的表皮转氨酶活性和TOC角质形成细胞中对葡萄球菌感染的增强的抗性。这些特征中的许多与TOC表皮中组成性伤口愈合样表型的存在一致，这可能揭示皮肤修复、再生和炎症的新途径。
iRHOM2 is a highly conserved, catalytically inactive member of the Rhomboid family, which has recently been shown to regulate the maturation of the multi-substrate ectodomain sheddase enzyme ADAM17 (TACE) in macrophages. Dominant iRHOM2 mutations are the cause of the inherited cutaneous and oesophageal cancer-susceptibility syndrome tylosis with oesophageal cancer (TOC), suggesting a role for this protein in epithelial cells. Here, using tissues derived from TOC patients, we demonstrate that TOC-associated mutations in iRHOM2 cause an increase in the maturation and activity of ADAM17 in epidermal keratinocytes, resulting in significantly upregulated shedding of ADAM17 substrates, including EGF-family growth factors and pro-inflammatory cytokines. This activity is accompanied by increased EGFR activity, increased desmosome processing and the presence of immature epidermal desmosomes, upregulated epidermal transglutaminase activity and heightened resistance to Staphylococcal infection in TOC keratinocytes. Many of these features are consistent with the presence of a constitutive wound-healing-like phenotype in TOC epidermis, which may shed light on a novel pathway in skin repair, regeneration and inflammation.