Monteleone Mercedes, Stow Jennifer L, Schroder Kate
Institute for Molecular Bioscience, The University of Queensland, St Lucia 4072, Australia.
Institute for Molecular Bioscience, The University of Queensland, St Lucia 4072, Australia.
Cytokine. 2015 Aug;74(2):213-8. doi: 10.1016/j.cyto.2015.03.022. Epub 2015 Apr 25.
One of the most poorly understood processes in cell biology is the peculiar ability of specific leaderless proteins to be secreted via ER/Golgi-independent mechanisms ('unconventional protein secretion'). One such leaderless protein is the major immune-activating cytokine, interleukin-1β (IL-1β). Unusual amongst cytokines, IL-1β is expressed in the cytosol as an inactive precursor protein. It requires maturation by the caspase-1 protease, which itself requires activation upon immune cell sensing of infection or cell stress. Despite 25 years of intensive research into IL-1β secretory mechanisms, how it exits the cell is still not well understood. Here we will review the various mechanisms by which macrophages have been proposed to secrete IL-1 family cytokines, and the potential involvement of caspase-1 therein. Since aberrant IL-1β production drives inherited and acquired human diseases (e.g. autoinflammatory diseases, arthritic diseases, gout, Alzheimer's disease), elucidation of the IL-1β secretory pathway may offer new therapeutic opportunities for treatment across this wide range of human conditions.
细胞生物学中最难以理解的过程之一，是特定无信号肽蛋白质通过不依赖内质网/高尔基体的机制进行分泌的特殊能力（“非常规蛋白质分泌”）。主要免疫激活细胞因子白细胞介素-1β（IL-1β）就是这样一种无信号肽蛋白质。在细胞因子中，IL-1β不同寻常，它在细胞质中作为无活性的前体蛋白表达。它需要通过半胱天冬酶-1蛋白酶进行成熟，而半胱天冬酶-1本身在免疫细胞感知感染或细胞应激时需要激活。尽管对IL-1β分泌机制进行了25年的深入研究，但它如何离开细胞仍未得到很好的理解。在这里，我们将综述巨噬细胞分泌IL-1家族细胞因子的各种机制，以及半胱天冬酶-1在其中的潜在作用。由于异常的IL-1β产生会引发遗传性和后天性人类疾病（如自身炎症性疾病、关节炎疾病、痛风、阿尔茨海默病），阐明IL-1β分泌途径可能为治疗这些广泛的人类疾病提供新的治疗机会。
