title: Caspase-4 is required for activation of inflammasomes.
abstract: IL-1β and IL-18 are crucial regulators of inflammation and immunity. Both cytokines are initially expressed as inactive precursors, which require processing by the protease caspase-1 for biological activity. Caspase-1 itself is activated in different innate immune complexes called inflammasomes. In addition, caspase-1 activity regulates unconventional protein secretion of many other proteins involved in inflammation and repair. Human caspase-4 is a poorly characterized member of the caspase family, which is supposed to be involved in endoplasmic reticulum stress-induced apoptosis. However, its gene is located on the same locus as the caspase-1 gene, which raises the possibility that caspase-4 plays a role in inflammation. In this study, we show that caspase-4 expression is required for UVB-induced activation of proIL-1β and for unconventional protein secretion by skin-derived keratinocytes. These processes require expression of the nucleotide-binding domain leucine-rich repeat containing, Pyrin domain containing-3 inflammasome, and caspase-4 physically interacts with its central molecule caspase-1. As the active site of caspase-4 is required for activation of caspase-1, the latter most likely represents a substrate of caspase-4. Caspase-4 expression is also essential for efficient nucleotide-binding domain leucine-rich repeat containing, Pyrin domain containing-3 and for absent in melanoma 2 inflammasome-dependent proIL-1β activation in macrophages. These results demonstrate an important role of caspase-4 in inflammation and innate immunity through activation of caspase-1. Therefore, caspase-4 represents a novel target for the treatment of (auto)inflammatory diseases.
authors.affiliation: Department of Biology, Institute of Cell Biology, ETH Zurich, CH-8093 Zurich, Switzerland.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Sollberger
authors.forename: Gerhard E
authors.initials: GE
authors.lastname: Strittmatter
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kistowska
authors.forename: Lars E
authors.initials: LE
authors.lastname: French
authors.forename: Hans-Dietmar
authors.initials: HD
authors.lastname: Beer
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053471:Caspases, Initiator / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000276:immunology* / Q000378:metabolism*; D020382:Interleukin-18 / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000071198:Pyrin; D034622:RNA Interference; D034741:RNA, Small Interfering; D014466:Ultraviolet Rays
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; C000604192:MEFV protein, human; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D000071198:Pyrin; D034741:RNA, Small Interfering; C093516:CASP4 protein, human; D053471:Caspases, Initiator; D020170:Caspase 1