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，它参与了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，但它们也在细胞外被发现，并通过一个活跃的过程释放出来。我们假设，细胞外热休克蛋白输出“警报”免疫系统，局部应激或损伤已经发生。因此，免疫系统会在局部损伤扩散的情况下进行及时的反应。我们创造了这种感知应力的系统机制——应力观测系统（SOS）。SOS的一个重要特征是热休克蛋白的释放与来源于质膜的细胞外囊泡（ECV）相关。这些囊泡包含针对特定细胞类型的信息，以传递压力信息。先前的研究表明，热休克蛋白家族的主要诱导形式Hsp70 （Hsp72）被发现嵌入从应激恢复的细胞的质膜中。此外，Hsp70可以插入到人工脂质双分子层中，打开离子传导途径。此外，Hsp70从与ECV相关的细胞中释放出来。hsp70阳性的ECV能够与巨噬细胞相互作用，诱导细胞改善、预防或保护机体免受随后的损伤，这与hsp70在应激耐受中的作用是一致的。本申请的目的是阐明Hsp70插入质膜和ECV释放以及与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，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。了解这种新型的通讯系统可能有助于对危重病人的诊断和治疗。

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.