Hippo signaling as a critical regulator of lupus keratinocyte dysfunction

Hippo 信号作为狼疮角质形成细胞功能障碍的关键调节因子

• 批准号: 10536347
• 负责人: Joanne Michelle Kahlenberg
• 金额: $ 46.68万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-02 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10536347
• 关键词: Address; Apical; Apoptosis; Apoptotic; Automobile Driving; Behavior; Biology; CASP3 gene; CASP8 gene; Cells; Characteristics; Chromatin; Chronic; Cutaneous Lupus Erythematosus; Data; Disease; Exhibits; FOXO1A gene; FOXO3A gene; Flare; Fostering; Functional disorder; Genetic; Genetic Transcription; Goals; IRF3 gene; Inflammation; Inflammatory Response; Interferon Type I; Interferons; Knowledge; LATS1 gene; Lead; Lesion; Literature; Lupus; Malignant Neoplasms; Mediating; Mediator of activation protein; Mission; Nucleic Acids; Organ; Pathogenicity; Pathologic; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Photosensitivity; Prevention; Production; Proteins; Public Health; Reporting; Research; Risk; Role; Secondary to; Signal Pathway; Signal Transduction; Skin; Stimulator of Interferon Genes; Systemic Lupus Erythematosus; TBK1 gene; TRAF6 gene; Therapeutic; Ubiquitination; Ultraviolet B Radiation; United States National Institutes of Health; Up-Regulation; Virus Diseases; Work; barrier to care; chemokine; cytokine; disability; improved; in vivo; in vivo Model; inhibitor; keratinocyte; kinase inhibitor; lupus cutaneous; member; novel; novel therapeutics; overexpression; prevent; response; side effect; skin disorder; skin lesion

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.

项目总结/摘要 系统性红斑狼疮（SLE）患者的非皮损和皮损皮肤富含I型干扰素 干扰素（IFN），其有助于炎症、凋亡和光敏性的倾向。重要的是，虽然新 目前已批准药物用于全面阻断SLE中I型IFN信号传导，它们的作用可能是中等的， 包括病毒感染风险在内的副作用仍然是治疗的障碍。此外，虽然干扰素是 重要的是，关于什么调节干扰素产生的倾向， SLE皮肤炎症。解决这一差距将导致对CLE病变的机械理解， 有针对性地精确消除致病因素，而没有副作用，例如全球性的 干扰素阻断，并可能预防疾病。我们新的初步数据揭示了功能性 SLE角质形成细胞中Hippo信号通路通过顶关键蛋白的过度表达而失调 调节因子，含WW结构域的蛋白1（WWC 1），导致Hippo信号传导的慢性过度活化， 增加的Yes相关蛋白（雅普）磷酸化。我们的数据还表明，这种倾斜的雅普， 磷酸化可能是SLE中已确定的异常凋亡反应的关键 角质形成细胞虽然这些数据本身就很有影响力，但最近的癌症文献报告也表明， Hippo途径的成员可能是通过与IFN的相互作用而产生I型IFN的关键调节剂。 cGAS/STING途径5，6.事实上，我们的初步数据将SLE-IFN-κ的过度生产确定为STING-1。 通过LATS 1/2抑制作用依赖和阻断雅普磷酸化，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 是狼疮角质形成细胞功能障碍的关键驱动因素， 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一假设 目的1：揭示Hippo通路在驱动增强的SLE角质形成细胞中的作用 凋亡目的2：确定Hippo信号传导扭曲I型胶原蛋白产生的机制。 SLE角质形成细胞中的干扰素。目的3：探讨Hippo信号通路在UVB介导的NF-κB-κB损伤中的作用。 引发炎症反应。成功完成这项提案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通路靶标， 作为预防和治疗SLE皮肤病的新靶点。