Mechanism and Repertoire of Apoptosis-Associated Speck-Like Protein Containing a Caspase Recruitment Domain-Mediated Gene Expression

Apoptosis associated speck-like protein containing a caspase recruitment domain (ASC) is an adaptor molecule that mediates inflammatory and apoptotic signals. Although the role of ASC in caspase-1-mediated IL-1β and IL-18 maturation is well known, ASC also induces NF-κB activation and cytokine gene expression in human cells. Here we investigated the molecular mechanism and repertoire of ASC-induced gene expression in human cells. We found that the specific activation of ASC induced AP-1 activity, which was required for optimal IL8 promoter activity. ASC activation also induced STAT3but not STAT1-, interferon-stimulated gene factor 3-, or NFAT-dependent reporter gene expression. The ASC-mediated AP-1 activation was NF-κB-independent and primarily cell-autonomous response, while the STAT3 activation required NF-κB activation and was mediated by a factor that can act in a paracrine manner. ASC-mediated AP-1 activation was inhibited by chemical or protein inhibitors for caspase-8, caspase-8-targeting small interfering RNA (siRNA), and p38and JNK-inhibitors, but not by a caspase-1 inhibitor, caspase-9or FADD -dominant-negative mutants, FADD or RICK-targeting siRNAs, or a MEK inhibitor, indicating that the ASC-induced AP-1 activation is mediated by caspase-8, p38, and JNK, but does not require caspase-1, caspase-9, FADD, RICK, or ERK. DNA microarray analyses identified 75 genes that were induced by ASC activation. A large proportion of them were related to transcription (23%), inflammation (21%), or cell death (16%), indicating that ASC is a potent inducer of inflammatory and cell death-related genes. This is the first report of ASC-mediated AP-1 activation and the repertoire of genes induced downstream of ASC activation.