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J Immunol. 2006 Apr 15;176(8):4979-86.

ASC directs NF-kappaB activation by regulating receptor interacting protein-2 (RIP2) caspase-1 interactions.

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  • 1Davis Heart and Lung Research Institute, The Ohio State University, Columbus 43210, USA.

Abstract

Receptor interacting protein-2 (RIP2) is a caspase recruitment domain (CARD)-containing kinase that interacts with caspase-1 and plays an important role in NF-kappaB activation. Apoptosis-associated speck-like protein containing a CARD (ASC) is a PYRIN and CARD-containing molecule, important in the induction of apoptosis and caspase-1 activation. Although RIP2 has also been linked to caspase-1 activation, RIP2 knockout animals fail to show a defect in caspase-1-mediated processing of proIL-1beta to its active form. Therefore, RIP2 function in binding to caspase-1 remains poorly understood. We hypothesized that caspase-1 may serve as a scaffolding molecule that promotes RIP2 interaction with IkappaB kinase-gamma thus inducing NF-kappaB activation. We further hypothesized that ASC, which also interacts with caspase-1 via its CARD, may interfere with the caspase-1 RIP2 interaction. In HEK293 cells, ASC induced prominent activation of caspase-1 and proIL-1beta processing. RIP2 transient transfection induced transcription of an NF-kappaB reporter gene. This RIP2-induced NF-kappaB activity and caspase-1 binding was inhibited in a dose-dependent fashion by ASC. Consistent with a role for caspase-1 as a scaffold for RIP2, caspase-1 knockout macrophages were suppressed in their ability to activate NF-kappaB, and septic caspase-1 knockout animals produced less IL-6, a functional marker of NF-kappaB activity. Lastly, THP-1 cells treated with small interfering RNA for ASC decreased their caspase-1 activity while enhancing their NF-kappaB signal. These data suggest that ASC may direct caspase-1 away from RIP2-mediated NF-kappaB activation, toward caspase-1-mediated processing of proIL-1beta by interfering with the RIP2 caspase-1 interaction.

PMID:
16585594
[PubMed - indexed for MEDLINE]
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