Hippo signaling as a critical regulator of lupus keratinocyte dysfunction

项目概要/摘要 系统性红斑狼疮（SLE）患者的非病变和病变皮肤富含I型干扰素 （干扰素）有助于炎症、细胞凋亡和光敏性的倾向。重要的是，虽然是新的 药物现已被批准用于全球性阻断 SLE 中的 I 型 IFN 信号传导，其作用可能是中等的， 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 重要的是，对于什么调节干扰素的产生和倾向存在着严重的知识差距。 SLE 皮肤炎症。解决这一差距将导致对 CLE 病变的机制理解，从而可以 有针对性地精确消除致病因素，而不会产生副作用，例如全球产生的致病因素 干扰素阻断，并有可能预防疾病。我们新颖的初步数据揭示了功能性的作用 SLE 角质形成细胞中 Hippo 信号通路因顶键过度表达而失调 调节器，含有 WW 结构域的蛋白 1 (WWC1)，导致 Hippo 信号传导慢性过度激活， Yes 相关蛋白 (YAP) 的磷酸化增加。我们的数据还表明 YAP 的这种偏差 磷酸化可能对于 SLE 中发现的异常细胞凋亡反应至关重要 角质形成细胞。虽然这些数据本身就具有影响力，但癌症文献中最近的报告也表明： Hippo 通路的成员可能通过与 I 型干扰素相互作用而成为 I 型干扰素产生的关键调节者 cGAS/STING 途径5,6。事实上，我们的初步数据将 SLE 过量产生 IFN-κ 确定为 STING- 通过抑制 LATS1/2 来依赖和阻断 YAP 磷酸化足以阻断 IFNK STING 激活后的转录。这些数据构成了我们总体假设的基础，即失调 Hippo 信号传导是狼疮角质形成细胞功能障碍的关键驱动因素，并且关键 Hippo- 的调节 信号传导介质将使狼疮角质形成细胞行为“正常化”。我们将通过以下方式解决这个假设 目标如下： 目标 1：揭示 Hippo 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 Hippo 信号传导影响 I 型蛋白产生的机制 SLE 角质形成细胞中的干扰素。目标 3：确定 Hippo 信号在 UVB 介导的 NF-κB- 中的作用 驱动的炎症反应。该提案的成功完成将揭示重要的新生物学 关于 I 型 IFN 和 Hippo 信号传导的相互作用，并确定特定的 Hippo 通路目标，这些目标将 成为预防和治疗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.