How the endocytic network mediates specificity of cell signaling

摘要：内吞网络如何调节细胞信号转导的特异性 受体串扰--两个或更多受体之间的合作以调节细胞反应--是一个关键 信令机制。它使细胞能够生成具有特定信号的大型组合曲目 受体的种类有限。受体串扰在细胞生理学中起着至关重要的作用。因此， 受体串扰功能障碍与许多人类疾病有关，例如传染病。 (包括新冠肺炎)、癌症和心血管疾病。为了了解其物理机制， 来自不同受体的信号在串扰中整合，研究仅集中在受体上 质膜上的相互作用。相比之下，串扰信号是如何高保真地转换的 从质膜到细胞核，人们对此知之甚少，也鲜有人探索。 本研究的总体目标是建立内细胞网络在信号转导和转录中的作用。 调节受体串扰。在之前的ESI-R35支持下，我们团队取得了开创性的发现 支持这样一个中心假设，即细胞外的化学物质和 物理刺激相互交织以调节受体串扰。具体地说，我们报道了一种新的模型，在这种模型中 受体可以通过在离散的信号簇之间形成重叠的接口来进行串扰，从而挑战 流行的观点认为，受体寡聚为串扰。重要的是，这种空间组织的相互作用 内小体和质膜上的受体受细胞外物理信号的调节，并直接 调节细胞的炎症反应。这些先前的发现和我们过多的新方法 为研究内体功能而开发的，为我们解决 知识鸿沟：内吞网络如何调节受体串扰？我们将解决如何 内吞网络从受体串音(方向1)和信号转导中协调化学信号 细胞外物理提示，以细化串扰信号的特异性(方向2)。要解决第一个问题 方向，我们将定义内吞分选，集体内小体细胞器的物理机制 相互作用和内小体特异性激活调制源自血浆的串扰信号 薄膜。为了解决第二个方向，我们将把实验与计算建模相结合，以 确定调节受体的内吞网络和细胞-基质相互作用之间的反馈回路 相声。这个项目将建立一种机械的和预测性的理解，了解内吞细胞网络是如何 调节受体串扰和细胞信号的时空特异性；这是一个很差的话题 明白了。它还将降低阻碍这一主题研究的技术壁垒，建立新的 用于在多个长度尺度上解剖内吞细胞网的动力学和功能的定量工具集。 最终，更好地了解内体在受体串扰中的功能将有助于发展 疾病的新治疗策略，如癌症治疗的免疫佐剂和疫苗。

Abstract: How the endocytic network mediates specificity of cell signaling Receptor crosstalk – the cooperation between two or more receptors to modulate cell responses – is a key signaling mechanism. It enables cells to generate a large combinatorial repertoire of specific signaling with a limited variety of receptors. Receptor crosstalk plays an essential role in cell physiology. Consequently, dysfunctions in receptor crosstalk are associated with many human diseases, such as infectious diseases (including COVID-19), cancer, and cardiovascular diseases. To understand the physical mechanisms by which signals from different receptors are integrated in crosstalk, studies have exclusively focused on receptor interactions at the plasma membrane. In contrast, how the crosstalk signals are transduced with high fidelity from the plasma membrane to the nucleus is poorly understood and scarcely explored. The overall goal of this research is to establish the functional role of the endocytic network in transducing and regulating receptor crosstalk. Under the prior ESI-R35 support, our group has made pioneering discoveries in support of the central hypothesis that the endocytic network is where extracellular chemical and physical stimuli intertwine to regulate receptor crosstalk. Specifically, we reported a new model in which receptors can crosstalk by forming overlapping interfaces between discrete signaling clusters, challenging the prevailing view that receptors oligomerize to crosstalk. Importantly, such spatially organized interaction between receptors at endosomes and plasma membranes is modulated by extracellular physical cues, and directly regulates cell inflammatory responses. These prior discoveries and the plethora of new approaches we developed for studying endosome functions laid a critical and unique foundation for us to address the knowledge gap: how does the endocytic network mediate receptor crosstalk? We will address how the endocytic network orchestrates chemical cues from receptor crosstalk (Direction 1), and transduces extracellular physical cues to refine the specificity of crosstalk signaling (Direction 2). To address the first direction, we will define the physical mechanisms by which endocytic sorting, collective endosome-organelle interactions, and endosome-specific activation modulate crosstalk signaling originated from the plasma membrane. To address the second direction, we will integrate experiments with computational modeling to determine the feedback loop between the endocytic network and cell-matrix interactions that regulate receptor crosstalk. This project will establish a mechanistic and predictive understanding of how the endocytic network mediates the spatiotemporal specificity of receptor crosstalk and cell signaling in general; a topic that is poorly understood. It will also lower the technical barrier that has impeded research on this topic, by establishing novel quantitative toolsets for dissecting the dynamics and function of the endocytic network on multiple length scales. Ultimately, a better understanding of endosome functions in receptor crosstalk will facilitate the development of new therapeutic strategies for diseases, such as immune adjuvants for cancer therapies and vaccines.