Role of Spink6 in tissue kallikrein mediated epidermal desquamation and inflammation

Spink6 在组织激肽释放酶介导的表皮脱屑和炎症中的作用

• 批准号: 161692752
• 负责人: Privatdozent Dr. Ulf Meyer-Hoffert, Ph.D.
• 金额: --
• 依托单位: Klinik für Dermatologie, Venerologie und Allergologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/161692752?language=en
• 关键词: Role; Spink6; tissue; kallikrein; mediated

Proteases of the KLK-family (Kallikrein related peptidases) have been implicated in the desquamation process of healthy human skin by cleaving desmosomal proteins. Their activity is tightly regulated by different mechanisms including specific protease inhibitors. Deregulation can lead to serious inflammatory diseases like the Netherton Syndrome, where the KLK-specific inhibitor LEKTI (lymphoepithelial inhibitor of Kazal-type) encoded by the gene spink5 (serine protease inhibitor of Kazal-type) is missing. The increased proteolytic activity leads to activation of the protease activated receptor-2, increased activation of proinflammatory products of the alarmin cathelicidin and to enhanced processing of members of the IL-1 family. In previous studies we have discovered two novel members of the SPINK family in human skin, namely SPINK6 and SPINK9. SPINK9 is a selective KLK5 inhibitor, whereas SPINK6 is the most potent inhibitor of several KLKs described so far. We characterized their mouse homologues as mouse mouse Spink12 for human SPINK9 and the highly conserved mouse Spink6 (homologue to human SPINK6). The inhibition profile of mouse Spink6 was similar to human SPINK6 but exhibited some differences, e.g. KLK4 was not inhibited by the human but very efficiently by the mouse Spink6. Interestingly, we detected cleavage of IL-1 family members like IL-36gamma by KLKs. KLK7 cleaved IL-36gamma within seconds whereas IL-36gamma cleavage by the tryptic KLK5 took hours. We suspect a regulatory mechanism by different KLKs for IL-36gamma activation in the epidermis. We therefore plan to further analyze the mechanism by which KLKs cleave IL-1 family members like IL-36gamma and want to explore the role of Klk-regulation by Spink6 using Spink6-/- mice in vivo.

klk家族的蛋白酶（Kallikrein相关肽酶）通过切割桥粒体蛋白参与健康人类皮肤的脱屑过程。它们的活性受到不同机制的严格调控，包括特定的蛋白酶抑制剂。放松管制可导致严重的炎症性疾病，如内瑟顿综合征，其中由spink5 （kazal型丝氨酸蛋白酶抑制剂）基因编码的klk特异性抑制剂LEKTI （kazal型淋巴上皮抑制剂）缺失。蛋白水解活性的增加导致蛋白酶激活受体-2的激活，警报素cathelicidin的促炎产物的激活增加，以及IL-1家族成员的加工增强。在之前的研究中，我们在人类皮肤中发现了SPINK家族的两个新成员，即SPINK6和SPINK9。SPINK9是一种选择性KLK5抑制剂，而SPINK6是迄今为止所描述的几种klk中最有效的抑制剂。我们将它们的小鼠同源物鉴定为小鼠Spink12（与人类SPINK9同源）和高度保守的小鼠Spink6（与人类Spink6同源）。小鼠Spink6的抑制谱与人Spink6相似，但也存在差异，如KLK4不被人抑制，而被小鼠Spink6有效抑制。有趣的是，我们检测到IL-1家族成员如IL-36gamma被KLKs切割。KLK7在几秒钟内切割IL-36gamma，而色氨酸KLK5切割IL-36gamma需要几个小时。我们怀疑不同的klk对表皮中il -36 γ激活的调节机制。因此，我们计划进一步分析KLKs切割IL-1家族成员如IL-36gamma的机制，并利用Spink6-/-小鼠在体内探索Spink6对klk的调控作用。

项目成果

The solution structure of the kallikrein-related peptidases inhibitor SPINK6.

• DOI: 10.1016/j.bbrc.2016.01.172
• 发表时间: 2016-02-26
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Jung S;Fischer J;Spudy B;Kerkow T;Sönnichsen FD;Xue L;Bonvin AM;Goettig P;Magdolen V;Meyer-Hoffert U;Grötzinger J
• 通讯作者: Grötzinger J

The serine protease inhibitor of Kazal-type 7 (SPINK7) is expressed in human skin

Kazal 7 型丝氨酸蛋白酶抑制剂 (SPINK7) 在人体皮肤中表达

• DOI: 10.1007/s00403-017-1773-9
• 发表时间: 2017-08
• 期刊: Archives of Dermatological Research
• 影响因子: 3
• 作者: Clemens Weber;Jan Fischer;Lisa Redelfs;Franziska Rademacher;Jürgen Harder;Stephan Weidinger;Zhihong Wu;Ulf Meyer‑Hoffer
• 通讯作者: Ulf Meyer‑Hoffer

Gingipains of Porphyromonas gingivalis Affect the Stability and Function of Serine Protease Inhibitor of Kazal-type 6 (SPINK6), a Tissue Inhibitor of Human Kallikreins*

牙龈卟啉单胞菌的牙龈蛋白酶影响 Kazal 6 型丝氨酸蛋白酶抑制剂 (SPINK6)（一种人激肽释放酶的组织抑制剂）的稳定性和功能*

• DOI: 10.1074/jbc.m116.722942
• 发表时间: 2016
• 期刊: The Journal of Biological Chemistry
• 作者: Plaza K;Kalinska M;Bochenska O;Meyer-Hoffert U;Fischer J;Falkowski K;Sasiadek L;Bielecka E;Potempa B;Kozik A;Potempa J;Kantyka T
• 通讯作者: Kantyka T