Keratin 14-dependent disulfides regulate epidermal homeostasis and barrier function via 14-3-3σ and YAP1
Keratin 14-dependent disulfides regulate epidermal homeostasis and barrier function via 14-3-3σ and YAP1
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DOI：
10.7554/elife.53165
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发表时间：
2020-05-05
期刊：
影响因子：
7.7
通讯作者：
Coulombe, Pierre A.
中科院分区：
文献类型：
--
作者：
Guo, Yajuan;Redmond, Catherine J.;Coulombe, Pierre A.
中间丝蛋白角蛋白14（K14）在表皮的基底角质形成细胞中提供重要的结构支持。最近的研究证明了K14依赖性二硫键在皮肤角质形成细胞中角蛋白IF的组织和动力学中的作用。在这里，我们报告说，在Krt 14的密码子373（C373 A）的半胱氨酸到丙氨酸取代的基因敲入小鼠表现出二硫键键结合的K14物种和屏障缺陷的改变继发于增强的增殖，更快的通过时间和改变表皮分化。蛋白质组学筛选将14-3-3鉴定为K14相互作用蛋白。后续研究表明，YAP 1是皮肤角质形成细胞中由14-3-3sigma调节的Hippo信号传导的转录效应子，在分化Krt 14 C373 A角质形成细胞中显示出异常的亚细胞分配和功能。K14中的残基C373在角蛋白的一个亚类中是保守的，被揭示为在早期分化的角质形成细胞中角蛋白组织和雅普功能的新调节剂，对表皮中的细胞力学、稳态和屏障功能具有影响。
The intermediate filament protein keratin 14 (K14) provides vital structural support in basal keratinocytes of epidermis. Recent studies evidenced a role for K14-dependent disulfide bonding in the organization and dynamics of keratin IFs in skin keratinocytes. Here we report that knock-in mice harboring a cysteine-to-alanine substitution at Krt14's codon 373 (C373A) exhibit alterations in disulfide-bonded K14 species and a barrier defect secondary to enhanced proliferation, faster transit time and altered differentiation in epidermis. A proteomics screen identified 14-3-3 as K14 interacting proteins. Follow-up studies showed that YAP1, a transcriptional effector of Hippo signaling regulated by 14-3-3sigma in skin keratinocytes, shows aberrant subcellular partitioning and function in differentiating Krt14 C373A keratinocytes. Residue C373 in K14, which is conserved in a subset of keratins, is revealed as a novel regulator of keratin organization and YAP function in early differentiating keratinocytes, with an impact on cell mechanics, homeostasis and barrier function in epidermis.