Abstract

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.

Keywords

BiologyCell biologySecretionCytoprotectionCaspase 1Proinflammatory cytokineCaspaseEndoplasmic reticulumInflammationInnate immune systemInflammasomeApoptosisImmunologyBiochemistryProgrammed cell deathImmune system

MeSH Terms

AnimalsCOS CellsCaspase 1Cell LineChlorocebus aethiopsFibroblast Growth Factor 2HumansInflammationInterleukin-1alphaKeratinocytesMacrophagesMiceProtein BindingProtein Sorting SignalsProteomicsRNASmall Interfering

Affiliated Institutions

Related Publications

Interleukin-1

Charles A. Dinarello

Interleukin-1 (IL-1) is the prototypic pro-inflammatory cytokine. There are two forms of IL-1, IL-1alpha and IL-1beta and in most studies, their biological activities are indist...

1997 Cytokine & Growth Factor Reviews 576 citations

Publication Info

Year
2008
Type
article
Volume
132
Issue
5
Pages
818-831
Citations
833
Access
Closed

External Links

Download PDF (Free) View on DOI.org PubMed Semantic Scholar

Social Impact

Altmetric
PlumX Metrics

Social media, news, blog, policy document mentions

Citation Metrics

833
OpenAlex
41
Influential
728
CrossRef

Cite This

Martin Keller, Andreas Rüegg, Sabine Werner et al. (2008). Active Caspase-1 Is a Regulator of Unconventional Protein Secretion. Cell , 132 (5) , 818-831. https://doi.org/10.1016/j.cell.2007.12.040

Identifiers

DOI
10.1016/j.cell.2007.12.040
PMID
18329368

Data Quality

Data completeness: 86%