Caspase-1 Activates Nuclear Factor of the κ-Enhancer in B Cells Independently of Its Enzymatic Activity*

By M. Lamkanfi, M. Kalai, X. Saelens, W. Declercq, Peter Vandenabeele. Journal of Biological Chemistry, 2004

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The proteolytic activity of caspases is involved in apoptosis and inflammation. In this regard, caspase-1 is required for pro-interleukin (IL)-1β and pro-IL-18 maturation. We report here on a novel function of caspase-1 as an activator of nuclear factor of the κ-enhancer in B-cells (NF-κB) and p38 mitogen-activated protein kinase (MAPK). This function is not shared by the murine caspase-1 homologues caspase-11 and -12. In contrast to pro-IL-1β maturation, caspase-1-induced NF-κB activation is not inhibited by the virus-derived caspase-1 inhibitor cytokine response modifier A and is equally induced by the enzymatically inactive caspase-1 C285A mutant. Although the general NF-κB-inhibiting protein A20 inhibits caspase-1-derived activation of NF-κB, dominant-negative forms of TRAF2 and RIP1 have no effect. We demonstrate that caspase-1 interacts with RIP2 and that dominant-negative forms of RIP2 and IκB kinase complex-β inhibit caspase-1-mediated NF-κB activation. Structure-function analysis shows that the caspase recruitment domain of caspase-1 mediates the activation of NF-κB and p38 MAPK. These data demonstrate that caspase-1 contributes to inflammation by two distinct pathways: proteolysis of pro-IL-1β, and RIP2-dependent activation of NF-κB and p38 MAPK mediated by the caspase recruitment domain.

View Paper: https://www.semanticscholar.org/paper/b25852256afd0f3204f73ed1a21fd5b8758cb94e

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  1. N. Van Opdenbosch
  2. M. Lamkanfi

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