Active caspase-1 is a regulator of unconventional protein secretion.
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.
Keller
Martin
M
Institute of Cell Biology, Department of Biology, ETH Zurich, CH-8093 Zurich, Switzerland.
Rüegg
Andreas
A
Werner
Sabine
S
Beer
Hans-Dietmar
HD
D000818:Animals; D019556:COS Cells; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D002460:Cell Line; D002522:Chlorocebus aethiops; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology; D053582:Interleukin-1alpha / Q000378:metabolism; D015603:Keratinocytes / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D011485:Protein Binding; D021382:Protein Sorting Signals; D040901:Proteomics; D034741:RNA, Small Interfering / Q000235:genetics
D053582:Interleukin-1alpha; D021382:Protein Sorting Signals; D034741:RNA, Small Interfering; D016222:Fibroblast Growth Factor 2; D020170:Caspase 1