A caspase activates secretion of many inflammatory response proteins without signal sequences, say Martin Keller, Hans-Dietmar Beer, and colleagues (Swiss Federal Institute of Technology, Zürich, Switzerland), revealing a new pathway for secretion. The cytokine interleukin-1α (IL-1α) has no secretion signal peptide but is nonetheless secreted as part of the inflammatory response. IL-1α is also not a substrate for caspase-1, but its secretion is reduced in macrophages that do not express the protease. In the new work, the authors showed that caspase-1 inhibition reduced secretion of IL-1α and almost 80 other inflammatory response proteins, many of which lack secretion signal peptides, including FGF-2. Many of the transported proteins were not caspase-1 substrates, yet catalytic activity of the enzyme was required for their secretion, for reasons that are not yet clear. Both IL-1α and FGF-2 bound to caspase-1, suggesting that the enzyme may carry them directly.

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