Inflammasome-dependent IL-1β release depends upon membrane permeabilisation.
Inflammasome-dependent IL-1β release depends upon membrane permeabilisation.
复制标题
DOI：
10.1038/cdd.2015.176
复制
发表时间：
2016-07
影响因子：
12.4
通讯作者：
Pelegrín P
中科院分区：
文献类型：
--
作者：
Martín-Sánchez F;Diamond C;Zeitler M;Gomez AI;Baroja-Mazo A;Bagnall J;Spiller D;White M;Daniels MJ;Mortellaro A;Peñalver M;Paszek P;Steringer JP;Nickel W;Brough D;Pelegrín P
白介素-1β (IL-1β) 是炎症反应的关键调节因子。 IL-1β不是通过传统的内质网-高尔基体蛋白分泌途径分泌的，迄今为止其释放机制尚不清楚。至关重要的是，其分泌取决于多分子炎性体复合物激活后前体形式的加工。使用IL-1β释放过程的新型可逆药理学抑制剂，结合生化、生物物理和实时单细胞共聚焦显微镜，以及表达金星标记的IL-1β的巨噬细胞，我们发现炎性体激活后IL-1β的分泌需要膜通透，并且与分泌细胞的死亡同时发生。因此，在巨噬细胞中，炎症小体激活后 IL-1β 的释放似乎是一个独立于细胞死亡过程中蛋白质非特异性泄漏的分泌过程。导致 IL-1β 释放的膜透化机制不同于其结构同源物成纤维细胞生长因子 2 (FGF2) 或 IL-1α 采用的非常规分泌机制，该过程涉及膜孔的形成，但不会导致细胞死亡。这些发现揭示了炎症反应启动的关键过程，并为蛋白质释放机制提供了新的见解。
Interleukin-1β (IL-1β) is a critical regulator of the inflammatory response. IL-1β is not secreted through the conventional ER–Golgi route of protein secretion, and to date its mechanism of release has been unknown. Crucially, its secretion depends upon the processing of a precursor form following the activation of the multimolecular inflammasome complex. Using a novel and reversible pharmacological inhibitor of the IL-1β release process, in combination with biochemical, biophysical, and real-time single-cell confocal microscopy with macrophage cells expressing Venus-labelled IL-1β, we have discovered that the secretion of IL-1β after inflammasome activation requires membrane permeabilisation, and occurs in parallel with the death of the secreting cell. Thus, in macrophages the release of IL-1β in response to inflammasome activation appears to be a secretory process independent of nonspecific leakage of proteins during cell death. The mechanism of membrane permeabilisation leading to IL-1β release is distinct from the unconventional secretory mechanism employed by its structural homologues fibroblast growth factor 2 (FGF2) or IL-1α, a process that involves the formation of membrane pores but does not result in cell death. These discoveries reveal key processes at the initiation of an inflammatory response and deliver new insights into the mechanisms of protein release.