Identification of CARDIAK, a RIP-like kinase that associates with caspase-1

Abstract

Members of the tumor necrosis factor receptor (TNFR) superfamily have an important role in the induction of cellular signals resulting in cell growth, differentiation and death [1]. TNFR-1 recruits and assembles a signaling complex containing a number of death domain (DD)-containing proteins, including the adaptor protein TRADD and the serine/threonine kinase RIP [2], which mediates TNF-induced NF-κB activation [3]. RIP also recruits caspase-2 to the TNFR-1 signaling complex via the adaptor protein RAIDD, which contains a DD and a caspase-recruiting domain (CARD) [4]. Here, we have identified a RIP-like kinase, termed CARDIAK (for CARD-containing interleukin (IL)-1β converting enzyme (ICE) associated kinase), which contains a serine/threonine kinase domain and a carboxy-terminal CARD [5]. Overexpression of CARDIAK induced the activation of both NF-κB and Jun N-terminal kinase (JNK). CARDIAK interacted with the TNFR-associated factors TRAF-1 and TRAF-2 and a dominant-negative form of TRAF-2 inhibited CARDIAK-induced NF-κB activation. Interestingly, CARDIAK specifically interacted with the CARD of caspase-1 (previously known as ICE), and this interaction correlated with the processing of pro-caspase-1 and the formation of the active p20 subunit of caspase-1. Together, these data suggest that CARDIAK may be involved in NF-κwB/JNK signaling and in the generation of the proinflammatory cytokine IL-1β through activation of caspase-1.