Communication of mechanical cues to the stress response in epidermal cells

机械信号与表皮细胞应激反应的通讯

• 批准号: 466075808
• 负责人: Professorin Dr. Carien Niessen, Ph.D.
• 金额: --
• 依托单位: Cluster of Excellence: Cellular Stress Responses in Aging-Associated Diseases
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/466075808?language=en
• 关键词: Communication; mechanical; cues; stress; response

The skin epidermis is exposed on a daily basis to external forces such as stretching or compression. The cells of the epidermis, keratinocytes, need to sense, communicate and respond to this mechanical challenge to maintain its barrier function to prevent e.g. infections or water loss. Adhesive junctions such as the cadherin-based adherens junctions and the actin cytoskeleton are key sensors and transducers of mechanical signals, and, as shown by us and others, important mediators of mechanical stress resistance. However, how junctions maintain healthy proteostasis to promote mechanical resistance is not known. We recently found that the polarity protein aPKC coordinates the dynamics of adhesive junctions and their associated cytoskeletal systems to control cell mechanics. Multilayered proteomics also showed that mammalian aPKCs interact with, phosphorylate and/or control protein levels of several chaperone proteins including BAG3 and HSPB8 previously implicated in mechanical stress-induced autophagy. Moreover, p62, a protein that targets cargo to autophagosomes, is a prominent direct binding partner of aPKCs, and loss of aPKClambda promotes autophagy. We thus hypothesize that sensing of mechanical force spatially regulates aPKC activity to coordinate of BAG3-dependent autophagy of damaged mechanosensitive proteins with AJ dynamics necessary to resist stress and maintain short and long-term tissue function. We will test this hypothesis in the epidermis using a unilateral stretch devise and micropatterns to apply mechanical stress to primary control and mutant keratinocytes, in addition to using in vivo mouse models. In close collaborations within this research unit we will investigate (a) the role of BAG3 and P62-dependent autophagy in mechanical stress response (B) define how aPKC regulates mechanical stress induced BAG3-dependent autophagy and junctional proteostasis and (C) examine physiological and pathological consequences of impaired mechanical stress responses. Together these studies will define how cells respond to mechanical stress to maintain tissue integrity, and whether healthy proteostasis of mechanosensitive units such as adherens junctions is essential for stress resistance.

皮肤表皮每天暴露于外力，例如拉伸或压缩。表皮的细胞，角质形成细胞，需要感知，交流和响应这种机械挑战，以保持其屏障功能，以防止例如感染或水分流失。粘附连接，如钙粘蛋白为基础的adherens连接和肌动蛋白细胞骨架是关键的传感器和机械信号的转换器，和，如我们和其他人所示，机械应力抗性的重要介质。然而，连接如何保持健康的蛋白稳态，以促进机械阻力是未知的。我们最近发现，极性蛋白aPKC协调动态的粘附连接及其相关的细胞骨架系统，以控制细胞力学。多层蛋白质组学还显示，哺乳动物aPKC与包括先前参与机械应力诱导的自噬的BAG 3和HSPB 8在内的几种伴侣蛋白相互作用、磷酸化和/或控制蛋白水平。 此外，p62是一种将货物靶向自噬体的蛋白质，是aPKC的主要直接结合伴侣，并且aPKC λ的缺失促进自噬。因此，我们假设机械力的感知在空间上调节aPKC活性，以协调受损机械敏感蛋白的BAG 3依赖性自噬与抵抗压力和维持短期和长期组织功能所需的AJ动力学。我们将测试这一假设在表皮中使用单向拉伸装置和微图案施加机械应力的主要控制和突变的角质形成细胞，除了使用在体内的小鼠模型。在本研究单位的密切合作中，我们将研究（a）BAG 3和P62依赖性自噬在机械应激反应中的作用（B）定义aPKC如何调节机械应激诱导的BAG 3依赖性自噬和连接蛋白稳态，以及（C）检查受损机械应激反应的生理和病理后果。这些研究将共同定义细胞如何响应机械应力以保持组织完整性，以及机械敏感单位（如粘附连接）的健康蛋白质稳态是否对抗应力至关重要。