Division of Molecular Psychoimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan; Department of Plastic and Reconstructive Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
Department of Plastic and Reconstructive Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
J Invest Dermatol. 2019 Feb;139(2):333-341. doi: 10.1016/j.jid.2018.07.044. Epub 2018 Sep 28.
Keloids mark a chronic inflammatory disease characterized by a fibroproliferative disorder of the skin. A genome-wide association study showed that single-nucleotide polymorphism rs8032158 in the neural precursor cell-expressed NEDD4 gene, which has six protein-coding transcript variants (TVs), is genetically linked to keloids. Here, we show that the high frequency of risk allele C in rs8032158 in keloid patients is associated with a selectively higher expression of TV3 of NEDD4 to activate the NF-κB pathway. Comparisons of keloid scars with normal skin samples that do not have the single-nucleotide polymorphism allele and were derived from different anatomical sites showed stronger expressions of NEDD4 TV3 and activated forms of NF-κB and STAT3 in keloid scars. Forced expression or selective knockdown of NEDD4 TV3 increased or decreased NF-κB activation in vitro. Furthermore, NEDD4 knockdown suppressed NF-κB-dependent inflammation development in vivo. Mechanistic analysis showed that NEDD4 TV3 is involved in NF-κB activation through its association with the adaptor protein RIP. These results suggest that NEDD4 TV3 is a potential diagnostic marker and therapeutic target for chronic skin diseases, including keloid.
瘢痕疙瘩是一种慢性炎症性疾病，其特征为皮肤的纤维增生性失调。一项全基因组关联研究表明，神经前体细胞表达的 NEDD4 基因中的单核苷酸多态性 rs8032158 与瘢痕疙瘩具有遗传相关性，该基因有六个蛋白编码转录变体（TV）。在这里，我们发现 rs8032158 中风险等位基因 C 在瘢痕疙瘩患者中的高频率与 NEDD4 的 TV3 的选择性更高表达有关，从而激活 NF-κB 通路。与不具有单核苷酸多态性等位基因且来自不同解剖部位的正常皮肤样本相比，瘢痕疙瘩瘢痕的 NEDD4 TV3 和激活形式的 NF-κB 和 STAT3 的表达更强。体外强制表达或选择性敲低 NEDD4 TV3 可增加或减少 NF-κB 的激活。此外，NEDD4 敲低可抑制体内 NF-κB 依赖性炎症的发展。机制分析表明，NEDD4 TV3 通过与接头蛋白 RIP 的关联而参与 NF-κB 的激活。这些结果表明，NEDD4 TV3 是包括瘢痕疙瘩在内的慢性皮肤病的潜在诊断标志物和治疗靶标。
