Caspases leave the beaten track: caspase-mediated activation of NF-kappaB

Abstract

The proteolytic activity of the cysteinyl aspartate-specific proteases, named caspases, mainly connotes their central role in apoptosis and inflammation. In this review we report on recent data on the role of caspases in the activation of nuclear factor kappaB (NF-kappaB), a transcription factor that fulfils a central role in innate and adaptive immunity, in cellular stress responses and in the induction of anti-apoptotic factors. Two different mechanisms by which caspases activate the NF-kappaB pathway are discussed.

Figure 1.

Overview of the main protein complexes leading to the activation of large prodomain caspases. Complex formation is initiated by different ligands and sustained by several interaction motifs harbored in complex-residing proteins. The ligand-sensing motifs (e.g., leucine-rich repeats, WD40 repeats, and CRRs) initiate the formation of oligomers. Death domain and death effector domain or CARD–CARD homotypic interactions are crucial for the recruitment and activation of either caspase-8 in the DISC or caspase-9 in the apoptosome, respectively. Caspase-1 or -5 is activated in the different inflammasomes using different adaptors such as ASC/ PYCARD or CARDINAL, depending on the type of inflammasome. Several compounds that lead to inflammasome activation, called PAMPs (pathogen-associated molecular patterns), such as bacterial RNA, LPS, or peptidoglycans, were identified. Caspase-2 is activated in the PIDDosome, using the adaptor molecule RAIDD upon DNA damage. How the nuclear damage triggers PIDDosome formation is currently not clear (see also text).

Figure 2.

Proposed model for caspase-mediated NF-κB activation. Multiple NF-κB signaling pathways can start from protein complexes containing the initiator caspases-1, -2, -8, or -10. These pathways can depend on limited caspase activation resulting in minor enzymatic activity, as in the case of TcR, B-cell receptor, or TLR stimulation, or can start from prodomain-mediated recruitment of NF-κB signaling molecules as in TNF signaling. In addition, cleavage of PARP-1 by caspase-3 or -7 contributes to the transactivation of the NF-κB complex. “Limited caspase activation” is complex-mediated caspase activation that considers only a small fraction of the total pool of a particular caspase and that remains associated with the complex (active caspase depicted by a zigzag line and orange color).