Lysyl Hydroxylase 3 Localizes to Epidermal Basement Membrane and Is Reduced in Patients with Recessive Dystrophic Epidermolysis Bullosa.
Lysyl Hydroxylase 3 Localizes to Epidermal Basement Membrane and Is Reduced in Patients with Recessive Dystrophic Epidermolysis Bullosa.
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DOI：
10.1371/journal.pone.0137639
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
South AP
中科院分区：
文献类型：
--
作者：
Watt SA;Dayal JH;Wright S;Riddle M;Pourreyron C;McMillan JR;Kimble RM;Prisco M;Gartner U;Warbrick E;McLean WH;Leigh IM;McGrath JA;Salas-Alanis JC;Tolar J;South AP
隐性营养不良性大疱性表皮病（RDEB）是由COL 7A 1突变引起的，导致VII型胶原蛋白减少或缺失、异常锚定原纤维形成和随后的真皮-表皮脆性。在这里，我们确定了一个显着减少PLOD 3的表达和其编码的蛋白质，胶原蛋白修饰酶赖氨酰羟化酶3（LH 3），在RDEB。我们显示了丰富的LH 3定位于正常皮肤中的基底膜，其在RDEB患者皮肤中严重耗尽。我们证明，表达是在部分调节内源性VII型胶原蛋白，并与以前的研究一致，即使是小的减少LH 3的表达导致显着减少分泌LH 3蛋白。外源性VII型胶原蛋白并没有改变培养的RDEB角质形成细胞中LH 3的表达，我们表明，接受骨髓移植的RDEB患者VII型胶原蛋白显着增加，但基底膜上的LH 3水平并没有增加。我们的数据报告了LH 3和内源性VII型胶原蛋白表达之间的直接联系，得出结论，RDEB患者基底膜LH 3的减少可能对疾病进展和治疗干预具有重要意义。
Recessive dystrophic epidermolysis bullosa (RDEB) is caused by mutations in COL7A1 resulting in reduced or absent type VII collagen, aberrant anchoring fibril formation and subsequent dermal-epidermal fragility. Here, we identify a significant decrease in PLOD3 expression and its encoded protein, the collagen modifying enzyme lysyl hydroxylase 3 (LH3), in RDEB. We show abundant LH3 localising to the basement membrane in normal skin which is severely depleted in RDEB patient skin. We demonstrate expression is in-part regulated by endogenous type VII collagen and that, in agreement with previous studies, even small reductions in LH3 expression lead to significantly less secreted LH3 protein. Exogenous type VII collagen did not alter LH3 expression in cultured RDEB keratinocytes and we show that RDEB patients receiving bone marrow transplantation who demonstrate significant increase in type VII collagen do not show increased levels of LH3 at the basement membrane. Our data report a direct link between LH3 and endogenous type VII collagen expression concluding that reduction of LH3 at the basement membrane in patients with RDEB will likely have significant implications for disease progression and therapeutic intervention.