Heat Shock Proteins and the Stress Observation System

描述（由申请人提供）：保持体内平衡是任何生物体的基本条件。最保守的细胞保护机制是热休克蛋白（hsp）的表达，它参与应激后关键细胞过程的修复和稳定。虽然热休克蛋白的主要功能局限于细胞内事件，但它们在细胞外被发现，通过一个活跃的过程释放。我们假设细胞外的热休克蛋白被输出以“警告”免疫系统局部的压力或损伤已经发生。因此，免疫系统准备好在局部损伤扩散的情况下及时做出反应。我们创造了这个系统的机制来感知压力，压力观察系统（SOS）。SOS的一个重要特征是hsp与来自质膜的细胞外囊泡（ECV）相关联地释放。这些囊泡含有靶向特定细胞类型的信息，用于传递应激信息。先前的研究表明，热休克蛋白70（热休克蛋白72），热休克蛋白家族的主要诱导形式，被发现嵌入细胞的质膜从应力恢复。此外，Hsp70还可以插入到人工脂质双层中，打开离子传导通路。此外，Hsp70从与ECV相关的细胞中释放。Hsp70阳性ECV能够与巨噬细胞（MS）相互作用，诱导启动细胞以改善、预防或保护生物体免受随后的损伤的反应，这与hsp在应激耐受中的作用一致。本申请的目的是阐明热休克蛋白70插入质膜和ECV释放和与M s相互作用的机制。这些研究将为蛋白质输出和免疫细胞激活提供新的细胞机制，这可能构成细胞生物学和生物医学研究的新知识支柱。此外，我们的研究可能会定义一个新的调节系统，该系统以囊泡的形式感知压力的发生，从而允许远距离细胞之间的通信。了解这种新的通信系统可能有助于危重患者的诊断和治疗。 公共卫生相关性：细胞外热休克蛋白是应激反应的一部分，但在系统水平。Hsp70被释放到循环中以警告生物体已经发生应激，并且循环中Hsp70的存在可以在局部损伤发生后引发先天免疫系统的细胞，以准备潜在的损伤传播并提供对后续应激的保护。

DESCRIPTION (provided by applicant): Preservation of homeostasis is a fundamental condition for any organism. The most conservative mechanism for cellular protection is the expression of heat shock proteins (hsp), which are involved in the repair and stabilization of key cellular processes after stress. Although the primary function of hsp is circumscribed to intracellular events, they have been found outside cells, released by an active process. We hypothesize that extracellular hsp are exported to "alert" the immune system that a localized stress or injury has occurred. Therefore, the immune system is primed to mount a timely response in case the localized insult should propagate. We have coined this systemic mechanism to sense stress the stress observation system (SOS). An important feature of the SOS is that hsp are released associated with extracellular vesicles (ECV) derived from the plasma membrane. These vesicles contain information for targeting specific cell types for the delivery of the stress information. Prior investigations have shown that Hsp70 (Hsp72), the major inducible form of the hsp family, was found embedded in the plasma membrane of cells recovering from a stress. In addition, Hsp70 can be inserted into artificial lipid bilayers, openin ion conductance pathways. Moreover, Hsp70 was released from cells associated with ECV. Hsp70-positive ECV is able to interact with macrophages (M s), inducing a response that primes cells to ameliorate, prevent, or defend the organism from subsequent insults, which is consistent with the role of hsp in stress tolerance. The objective of this application is to elucidate the mechanisms of Hsp70 insertion into the plasma membrane and ECV release and interaction with M s. These investigations will provide novel cellular mechanisms for protein export and activation of immune cells, which are likely to constitute new pillars of knowledge for cellular biology as well as biomedical research. Moreover, our studies may define a new regulatory system that senses the occurrence of stress in the form of vesicles that permit the communication between distant cells. An understanding of this novel communication system may be of help in the diagnosis and treatment of critically ill patients. PUBLIC HEALTH RELEVANCE: Extracellular hsp are part of the stress response, but at a systemic level. Hsp70 is released into circulation to alert the organism that stress has occurred, and the presence of Hsp70 in circulation may prime cells of the innate immune system after the occurrence of a localized injury to prepare for the potential propagation of the insult and offer protection from subsequent stresses.