Keller Martin, Rüegg Andreas, Werner Sabine, Beer Hans-Dietmar
Institute of Cell Biology, Department of Biology, ETH Zurich, CH-8093 Zurich, Switzerland.
Cell. 2008 Mar 7;132(5):818-31. doi: 10.1016/j.cell.2007.12.040.
Mammalian cells export most proteins by the endoplasmic reticulum/Golgi-dependent pathway. However, some proteins are secreted via unconventional, poorly understood mechanisms. The latter include the proinflammatory cytokines interleukin(IL)-1beta, IL-18, and IL-33, which require activation by caspase-1 for biological activity. Caspase-1 itself is activated by innate immune complexes, the inflammasomes. Here we show that secretion of the leaderless proteins proIL-1alpha, caspase-1, and fibroblast growth factor (FGF)-2 depends on caspase-1 activity. Although proIL-1alpha and FGF-2 are not substrates of the protease, we demonstrated their physical interaction. Secretome analysis using iTRAQ proteomics revealed caspase-1-mediated secretion of other leaderless proteins with known or unknown extracellular functions. Strikingly, many of these proteins are involved in inflammation, cytoprotection, or tissue repair. These results provide evidence for an important role of caspase-1 in unconventional protein secretion. By this mechanism, stress-induced activation of caspase-1 directly links inflammation to cytoprotection, cell survival, and regenerative processes.
哺乳动物细胞通过内质网/高尔基体依赖途径输出大多数蛋白质。然而，一些蛋白质是通过非常规的、了解甚少的机制分泌的。后者包括促炎细胞因子白细胞介素（IL）-1β、IL-18和IL-33，它们需要半胱天冬酶-1激活才能具有生物活性。半胱天冬酶-1本身由天然免疫复合物炎性小体激活。在此我们表明，无信号肽蛋白前白细胞介素-1α、半胱天冬酶-1和成纤维细胞生长因子（FGF）-2的分泌依赖于半胱天冬酶-1的活性。虽然前白细胞介素-1α和FGF-2不是该蛋白酶的底物，但我们证明了它们之间存在物理相互作用。使用iTRAQ蛋白质组学进行的分泌蛋白质组分析揭示了半胱天冬酶-1介导的其他具有已知或未知细胞外功能的无信号肽蛋白的分泌。引人注目的是，这些蛋白质中有许多参与炎症、细胞保护或组织修复。这些结果为半胱天冬酶-1在非常规蛋白质分泌中的重要作用提供了证据。通过这种机制，应激诱导的半胱天冬酶-1激活直接将炎症与细胞保护、细胞存活和再生过程联系起来。
