CARD games in apoptosis and immunity

Abstract

A bewildering array of proteins containing the caspase recruitment domain (CARD) have now been identified. Previously, CARD-CARD interactions have been shown to be involved in the assembly of protein complexes that promote caspase processing and activation in the context of apoptosis. However, as the family of CARD-containing proteins has grown, it has become apparent that the majority of these proteins do not recruit caspases or promote caspase activation. Instead, many participate in NF-kappaB signalling pathways associated with innate or adaptive immune responses. Here, we suggest a simplified classification of the CARD proteins based upon their domain structures and discuss the divergent roles of these proteins in the context of host defence.

Fig. 1. Schematic representation of the domain structures of human CARD-containing proteins. Proteins have been divided into four sub-groups based upon the domains they share and on their likely function as protein scaffolds, adaptors or decoy molecules (see text).

Fig. 2. Examples of pathways leading to either caspase or NF-κB activation. (I) In response to cell damage or stress, mitochondrial cytochrome c is released into the cytosol to provoke oligomerisation of Apaf-1 and caspase-9 (the apoptosome). Two examples of NF-κB activation pathways involving CARD proteins are shown. (IIa) Upon T- or B-cell receptor stimulation, signalling pathways are initiated that converge upon the bipartite protein Bcl10. Bcl10 promotes NF-κB activation most likely through recruitment of the IKK complex via MALT1. (IIb) A different route to NF-κB activation is initiated by LPS, derived from intracellular bacteria. This may trigger complex formation between Nod1 (or Nod2) and RICK. Recruitment of IKKγ to the complex, via RICK, probably results in assembly and activation of the IKK complex via a mechanism that has not been defined.

Seamus J. Martin & Lisa Bouchier-Hayes