Hippo signaling as a critical regulator of lupus keratinocyte dysfunction

项目摘要/摘要 系统性红斑狼疮(SLE)患者非皮损和皮损皮肤富含I型干扰素 (IFN)，它有助于炎症、细胞凋亡和光敏的倾向。重要的是，虽然是新的 药物现在被批准用于全球阻断SLE中的I型干扰素信号，它们的效果可能是温和的和 副作用，包括病毒感染的风险，仍然是治疗的障碍。此外，虽然干扰素是 重要的是，关于是什么调节干扰素的产生和倾向存在严重的知识差距 系统性红斑狼疮皮肤炎症。解决这一差距将导致对CLE损害的机械性理解， 有针对性地精准消除致病因素，而不会产生副作用，如全球 阻断干扰素，并有可能预防疾病。我们的新的初步数据揭示了功能 HIPPO信号通路在SLE角质形成细胞中的过度表达 调节子，WW结构域包含蛋白1(WWC1)，导致河马信号的慢性过度激活和 YAP的磷酸化增加。我们的数据还显示，YAP的这种倾斜 磷酸化可能是系统性红斑狼疮异常细胞凋亡反应的关键 角质形成细胞。虽然这些数据本身是有影响的，但最近癌症文献中的报告也表明 河马途径的成员可能是I型干扰素产生的关键调节因子，通过与 的确，我们的初步数据将系统性红斑狼疮-干扰素-κ的过度生产确定为-STIN- 通过抑制LATS1/2依赖和阻断YAP磷酸化足以阻断IFNK 刺痛激活后的转录。这些数据构成了我们总体假设的基础，即监管失调 河马信号是狼疮角质形成细胞功能障碍的关键驱动因素，而关键河马信号的调节- 信号介体将使狼疮角质形成细胞的行为“正常化”。我们将通过以下方式解决这一假设 以下目标：目标1：揭示河马通路在驱动SLE角质形成细胞增强中的作用 细胞凋亡。目标2：确定河马信号扭曲I型细胞产生的机制 系统性红斑狼疮角质形成细胞中的干扰素目的3：确定河马信号在UVB介导的NF-κB-2中的作用。 驱动炎症反应。这项研究的成功完成将发现重要的新生物学。 关于I型IFN和河马信号的相互作用，并确定特定的河马途径靶点 作为预防和治疗SLE皮肤病的新靶点。

PROJECT SUMMARY/ABSTRACT The non-lesional and lesional skin of systemic lupus erythematosus (SLE) patients is rich in type I interferons (IFNs) which contribute to a propensity for inflammation, apoptosis, and photosensitivity. Importantly, while new drugs are now approved for global blockade of type I IFN signaling in SLE, their effects may be moderate and side effects, including risk of viral infections, remain a barrier to treatment. Further, while interferons are important, there is a critical knowledge gap as to what regulates the propensity for interferon production and inflammation in SLE skin. Addressing this gap will lead to mechanistic understanding of CLE lesions that can be targeted to precisely eliminate the pathogenic players without side effects, such as those generated by global IFN blockade, and potentially prevent disease. Our novel preliminary data has uncovered a role for functional dysregulation of the Hippo signaling pathway in SLE keratinocytes through overexpression of the apical key regulator, WW domain containing protein 1 (WWC1), resulting in chronic overactivation of Hippo signaling and increased phosphorylation of Yes-associated protein (YAP). Our data also show that this skewing of YAP phosphorylation may be critical for the aberrant apoptotic responses that have been identified in SLE keratinocytes. While this data is impactful on its own, recent reports in the cancer literature also suggest that members of the Hippo pathway may be critical regulators of type I IFN production through interactions with the cGAS/STING pathway5,6. Indeed, our preliminary data identify SLE-overproduction of IFN-κ as STING- dependent and blockade of YAP phosphorylation through LATS1/2 inhibition as sufficient to block IFNK transcription after STING activation. These data form the basis of our overall hypothesis that dysregulation of Hippo signaling is a critical driver of lupus keratinocyte dysfunction and that modulation of key Hippo- signaling mediators will “normalize” lupus keratinocyte behavior. We will address this hypothesis through the following aims: Aim 1: Uncover the role of the Hippo pathway in driving enhanced SLE keratinocyte apoptosis. Aim 2: Determine the mechanisms by which Hippo signaling skews the production of type I interferons in SLE keratinocytes. Aim 3: Determine the role of Hippo signaling in UVB-mediated NF-κB- driven inflammatory responses. Successful completion of this proposal will uncover important new biology regarding the interaction of type I IFNs and Hippo signaling and identify specific Hippo pathway targets that will serve as novel targets for prevention and treatment of SLE skin disease.