Abstract：
Caspase recruitment domain family member 14 (CARD14) and its variants are associated with both atopic dermatitis (AD) and psoriasis, but their mechanistic impact on skin barrier homeostasis is largely unknown. CARD14 is known to signal via NF-κB; however, CARD14-NF-κB signaling does not fully explain the heterogeneity of CARD14-driven disease. Here, we describe a direct interaction between CARD14 and MYC and show that CARD14 signals through MYC in keratinocytes to coordinate skin barrier homeostasis. CARD14 directly binds MYC and influences barrier formation in an MYC-dependent fashion, and this mechanism is undermined by disease-associated CARD14 variants. These studies establish a paradigm that CARD14 activation regulates skin barrier function by two distinct mechanisms, including activating NF-κB to bolster the antimicrobial (chemical) barrier and stimulating MYC to bolster the physical barrier. Finally, we show that CARD14-dependent MYC signaling occurs in other epithelia, expanding the impact of our findings beyond the skin.
摘要：
Caspase募集域家族成员14（CARD14）及其变体与特应性皮炎（AD）和银屑病相关，但是它们对皮肤屏障稳态的机制影响在很大程度上是未知的。已知CARD14通过NF-κB发出信号；然而，CARD14-NF-κB信号不能完全解释CARD14驱动疾病的异质性。这里,我们描述了CARD14和MYC之间的直接相互作用，并显示CARD14通过角质形成细胞中的MYC信号来协调皮肤屏障稳态。CARD14直接结合MYC并以MYC依赖性方式影响屏障形成，这种机制被疾病相关的CARD14变异体破坏。这些研究建立了一个范式，即CARD14激活通过两种不同的机制调节皮肤屏障功能，包括激活NF-κB以增强抗微生物（化学）屏障和刺激MYC以增强物理屏障。最后,我们显示CARD14依赖性MYC信号发生在其他上皮，将我们发现的影响扩大到皮肤之外。
