Marciniak Stefan J, Ron David
Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
Physiol Rev. 2006 Oct;86(4):1133-49. doi: 10.1152/physrev.00015.2006.
The extracellular space is an environment hostile to unmodified polypeptides. For this reason, many eukaryotic proteins destined for exposure to this environment through secretion or display at the cell surface require maturation steps within a specialized organelle, the endoplasmic reticulum (ER). A complex homeostatic mechanism, known as the unfolded protein response (UPR), has evolved to link the load of newly synthesized proteins with the capacity of the ER to mature them. It has become apparent that dysfunction of the UPR plays an important role in some human diseases, especially those involving tissues dedicated to extracellular protein synthesis. Diabetes mellitus is an example of such a disease, since the demands for constantly varying levels of insulin synthesis make pancreatic beta-cells dependent on efficient UPR signaling. Furthermore, recent discoveries in this field indicate that the importance of the UPR in diabetes is not restricted to the beta-cell but is also involved in peripheral insulin resistance. This review addresses aspects of the UPR currently understood to be involved in human disease, including their role in diabetes mellitus, atherosclerosis, and neoplasia.
细胞外空间是一个对未修饰多肽充满敌意的环境。因此，许多通过分泌或在细胞表面展示而暴露于该环境的真核蛋白质需要在一种特殊的细胞器——内质网（ER）内进行成熟步骤。一种复杂的稳态机制，即未折叠蛋白反应（UPR），已经进化出来，以将新合成蛋白质的负荷与内质网使其成熟的能力联系起来。很明显，UPR功能障碍在一些人类疾病中起着重要作用，尤其是那些涉及专门进行细胞外蛋白质合成的组织的疾病。糖尿病就是这样一种疾病的例子，因为对不断变化的胰岛素合成水平的需求使胰腺β细胞依赖于有效的UPR信号传导。此外，该领域最近的发现表明，UPR在糖尿病中的重要性不仅限于β细胞，还涉及外周胰岛素抵抗。本综述探讨了目前已知与人类疾病相关的UPR的各个方面，包括它们在糖尿病、动脉粥样硬化和肿瘤形成中的作用。
