Cancer Institute of Traditional Chinese Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Department of Burns and Plastic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
FASEB J. 2019 Jan;33(1):163-174. doi: 10.1096/fj.201800353R. Epub 2018 Jul 3.
A key member of the sentrin/small ubiquitin-like modifier (SUMO)-specific protease (SENP) family, SENP2 has been shown to implicate embryonic development, fatty acid metabolism, atherosclerosis, and neurodegenerative diseases. However, other biologic functions of SENP2 and its specific targets are incompletely understood. Here, we uncovered a novel role of SENP2 in negative regulation of keratinocyte migration, a process crucial to wound epithelialization. Defects in this function are often associated with the clinical phenotypes of chronic nonhealing wounds. Mechanistically, SENP2 as a specific de-SUMOylase targets NDR1 (nuclear Dbf2-related 1), also called STK38 (serine-threonine kinase 38), for de-SUMOylation and SUMO conjugation of NDR1 on Lys-465 attenuates its inhibition of p38/ERK1/2 activation by decreasing the association of NDR1 with MEK kinase 1/2. Significantly, low-level laser (LLL) irradiation increases NDR1 SUMOylation and subsequent p38/ERK1/2 activation via down-regulation of SENP2, leading to faster keratinocyte migration. Our findings fill the gaps that linger in the basic mechanisms underlying LLL therapy.-Xiao, N., Li, H., Yu, W., Gu, C., Fang, H., Peng, Y., Mao, H., Fang, Y., Ni, W., Yao, M. SUMO-specific protease 2 (SENP2) suppresses keratinocyte migration by targeting NDR1 for de-SUMOylation.
SENP2 是一种重要的含小泛素样修饰物（SUMO）特异性蛋白酶（SENP）家族成员，其功能涉及胚胎发育、脂肪酸代谢、动脉粥样硬化和神经退行性疾病等多个方面。然而，SENP2 的其他生物学功能及其特定靶点尚不完全清楚。在这里，我们发现 SENP2 在调控角质形成细胞迁移方面发挥了新的作用，而角质形成细胞迁移是创伤上皮化过程中的关键步骤。这一功能的缺陷通常与慢性难愈性创面的临床表型有关。在机制上，SENP2 作为一种特异性去 SUMO 酶，靶向 NDR1（核 Dbf2 相关蛋白 1），又称 STK38（丝氨酸/苏氨酸激酶 38），通过去 SUMO 化和 SUMO 化修饰 NDR1 的 Lys-465，减弱其对 p38/ERK1/2 激活的抑制作用，减少 NDR1 与 MEK 激酶 1/2 的结合。重要的是，低水平激光（LLL）照射通过下调 SENP2 增加 NDR1 的 SUMO 化及其随后的 p38/ERK1/2 激活，从而促进角质形成细胞迁移。我们的研究结果填补了 LLL 治疗基本机制中存在的空白。-肖楠、李昊、于伟、顾晨、方慧、彭勇、毛海婷、方燕、倪伟、姚萌。SUMO 特异性蛋白酶 2（SENP2）通过靶向 NDR1 进行去 SUMO 化抑制角质形成细胞迁移。
