A keratin scaffold regulates epidermal barrier formation, mitochondrial lipid composition, and activity.
A keratin scaffold regulates epidermal barrier formation, mitochondrial lipid composition, and activity.
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DOI：
10.1083/jcb.201404147
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发表时间：
2015-12-07
期刊：
影响因子：
--
通讯作者：
Magin TM
中科院分区：
文献类型：
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作者：
Kumar V;Bouameur JE;Bär J;Rice RH;Hornig-Do HT;Roop DR;Schwarz N;Brodesser S;Thiering S;Leube RE;Wiesner RJ;Vijayaraj P;Brazel CB;Heller S;Binder H;Löffler-Wirth H;Seibel P;Magin TM
表皮角蛋白细丝是角化包膜的重要组成部分和组织者，通过调节其膜成分来调节线粒体的代谢。角蛋白中间丝(KIFs)保护表皮免受机械力的伤害，支持强大的黏附，帮助屏障的形成，并调节生长。I型和II型角蛋白对这些功能的作用机制尚不完全清楚。在这里，我们报告了缺乏I型或II型角蛋白的小鼠表现出严重的屏障缺陷和脆弱的皮肤，导致围产儿完全外露死亡。对出生前KtyI−/−和KtyII−/−K8小鼠角化包膜(CEs)的比较蛋白质组学研究表明，KIF的缺失导致了许多CE组分的失调，包括桥粒芯糖蛋白1的下调。尽管Clicrin持续表达，许多NRF2靶标上调，包括CE组分Sprr2d和Sprr2h，但广泛的屏障缺陷仍然存在，确定角蛋白是必需的CE支架。此外，我们发现Kifs以一种细胞固有的方式控制线粒体的脂组成和活性。因此，我们的研究通过将角蛋白支架与线粒体、粘连和CE形成联系起来，解释了伴随屏障障碍的角蛋白疾病的复杂性。
Epidermal keratin filaments are important components and organizers of the cornified envelope and regulate mitochondrial metabolism by modulating their membrane composition. Keratin intermediate filaments (KIFs) protect the epidermis against mechanical force, support strong adhesion, help barrier formation, and regulate growth. The mechanisms by which type I and II keratins contribute to these functions remain incompletely understood. Here, we report that mice lacking all type I or type II keratins display severe barrier defects and fragile skin, leading to perinatal mortality with full penetrance. Comparative proteomics of cornified envelopes (CEs) from prenatal KtyI−/− and KtyII−/−K8 mice demonstrates that absence of KIF causes dysregulation of many CE constituents, including downregulation of desmoglein 1. Despite persistence of loricrin expression and upregulation of many Nrf2 targets, including CE components Sprr2d and Sprr2h, extensive barrier defects persist, identifying keratins as essential CE scaffolds. Furthermore, we show that KIFs control mitochondrial lipid composition and activity in a cell-intrinsic manner. Therefore, our study explains the complexity of keratinopathies accompanied by barrier disorders by linking keratin scaffolds to mitochondria, adhesion, and CE formation.