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.

Caspases as the Key Effectors of Inflammatory Responses Against Bacterial Infection

“…One of the human orthologs of murine caspase-11, caspase-4 is required for the UVB-induced mature IL-1b secretion from skin-derived keratinocytes (Sollberger et al 2012). In the process of cytokine production, caspase-4 interacts with caspase-1, and this interaction is required for the activation of caspase-1 (Sollberger et al 2012).…”

“…In the process of cytokine production, caspase-4 interacts with caspase-1, and this interaction is required for the activation of caspase-1 (Sollberger et al 2012). Caspase-5 has also been shown to be required for caspase-1 activation using human retinal pigment epithelial cells stimulated with LPS/ATP (Bian et al 2011).…”

“…ICE cleaves pro-IL-1b to yield active cytokine; however, it does so in the absence of apoptosis induction (Black et al 1989a;Kostura et al 1989). Based on multiple reports revealing the functional roles and activation mechanisms of caspases, caspases are now divided into three functional groups: apoptosis induction (caspase-2, -3, -6, -7, -8, -9, and -10) (Guo et al 2002;Kischkel et al 2001;Parrish et al 2013), inflammatory responses (caspase-1, -4, -5, and -12) (Bian et al 2011;Black et al 1989a;Kostura et al 1989;Lamkanfi et al 2004;Sollberger et al 2012), and differentiation (caspase-14) (Denecker et al 2008) (Fig. 1).…”

Silver Nanoparticles Induce Degradation of the Endoplasmic Reticulum Stress Sensor Activating Transcription Factor-6 Leading to Activation of the NLRP-3 Inflammasome

“…These results indicate that AgNP-induced cell death is distinct from apoptosis. AgNP 15 Induce Pyroptosis and Activation of the Inflammasome-Knowing that activation of caspase-4 and caspase-7 is associated with activation of the inflammasome (13,29,30), in addition to the loss of membrane integrity observed after PI staining (this study), we next investigated the role of AgNP 15 in the activation of inflammasomes. Because pyroptosis, another type of cell death, is dependent on caspase-1, we also followed its processing as well as its activa- tion and other components of the NLRP-3 inflammasome.…”

Molecular mechanisms regulating NLRP3 inflammasome activation

“…59 Ultraviolet irradiation activates the NLRP3 inflammasome in keratinocytes 60 and ultraviolet B-induced caspase-4 is required for efficient NLRP3 inflammasome activation through interaction with and activation of caspase-1 in macrophages. 61 Recent studies showed that albumin triggers NLRP3 inflammasome activation in renal proximal tubular cells and downregulates tight junction proteins at the gene and protein levels, affecting renal tubular integrity. 62 Dietary intake of fatty acids and cellular lipid metabolism are associated with regulation of the NLRP3 inflammasome.…”