Cellular & Molecular Pathology, German Cancer Research Center, 69120 Heidelberg, Germany.
Hum Mol Genet. 2012 Feb 1;21(3):586-608. doi: 10.1093/hmg/ddr494. Epub 2011 Oct 28.
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.
角质层作为表皮的最外层，起到防止干燥和感染的作用。位于其下的角化包膜（CE）和细胞间脂质基质对这两个主要的保护屏障起着重要作用。具有超长链酰基部分（ULC-Cers）的表皮特有的神经酰胺是细胞外脂质层（ELL）的关键成分，并与 CE 蛋白结合，从而有助于形成角化脂质包膜（CLE）。在这里，我们确定了 CerS3（CerS1-6 中的一种）在体外和体内的 ULC-Cer 合成中是唯一必需的。CerS3 敲除的小鼠完全缺乏 ULC-Cers（≥C26），没有连续的 ELL，也没有功能正常的 CLE。因此，新生突变小鼠在出生后不久因经表皮水分流失而死亡。突变皮肤容易受到白色念珠菌感染，这突出表明 ULC-Cers 对两种屏障功能都至关重要。持续的表皮、过度角化和角化不全是突变皮肤的特征，表明 Cers 的缺失会导致角质形成细胞在胚胎前屏障阶段成熟停滞。
