Loss of ceramide synthase 3 causes lethal skin barrier disruption
Loss of ceramide synthase 3 causes lethal skin barrier disruption
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DOI：
10.1093/hmg/ddr494
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发表时间：
2012-02-01
影响因子：
3.5
通讯作者：
Sandhoff, Roger
中科院分区：
文献类型：
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作者：
Jennemann, Richard;Rabionet, Mariona;Sandhoff, Roger
角质层作为最外表皮层，可防止干燥和感染。底层的角质化包膜 (CE) 和细胞间脂质基质对这两个主要的保护屏障都有重要贡献。表皮特有的具有超长链酰基部分的神经酰胺 (ULC-Cers) 是细胞外脂质片层 (ELL) 的关键成分，并与 CE 蛋白结合，从而形成角质化脂质包膜 (CLE)。在这里，我们在 CerS1-6 中鉴定出了人和小鼠神经酰胺合酶 3 (CerS3)，它是体外 ULC-Cer 合成和小鼠体内 CerS3 合成所必需的。小鼠体内缺乏 CerS3 会导致 ULC-Cers (>= C26) 完全丧失、缺乏连续的 ELL 和无功能的 CLE。因此，新生的突变小鼠在出生后不久就会因经表皮失水而死亡。突变的皮肤容易受到白色念珠菌感染，这凸显了 ULC-Cers 对于两种屏障功能都至关重要。持续的周皮、角化过度和角质化缺陷是突变皮肤的标志，表明 Cers 的丢失会在胚胎前屏障阶段触发角质形成细胞成熟停滞。
The stratum corneum as the outermost epidermal layer protects against exsiccation and infection. Both the underlying cornified envelope (CE) and the intercellular lipid matrix contribute essentially to these two main protective barriers. Epidermis-unique ceramides with ultra-long-chain acyl moities (ULC-Cers) are key components of extracellular lipid lamellae (ELL) and are bound to CE proteins, thereby contributing to the cornified lipid envelope (CLE). Here, we identified human and mouse ceramide synthase 3 (CerS3), among CerS1-6, to be exclusively required for the ULC-Cer synthesis in vitro and of mouse CerS3 in vivo. Deficiency of CerS3 in mice results in complete loss of ULC-Cers (>= C26), lack of continuous ELL and a non-functional CLE. Consequently, newborn mutant mice die shortly after birth from transepidermal water loss. Mutant skin is prone to Candida albicans infection highlighting ULC-Cers to be pivotal for both barrier functions. Persistent periderm, hyperkeratosis and deficient cornification are hallmarks of mutant skin demonstrating loss of Cers to trigger a keratinocyte maturation arrest at an embryonic pre-barrier stage.