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)-1β, 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-1
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, caspase-1, and fibroblast growth factor (FGF)-2 depends on caspase-1 activity. Although proIL-1
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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.
