Caspase recruitment domain protein 6 is a microtubule-interacting protein that positively modulates NF-κB activation

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Abstract
Proteins containing a caspase recruitment domain (CARD) play pivotal roles in signal transduction leading to apoptosis and NF-κB activation and inflammation. Here we identify and characterize human and mouse CARD protein 6 (CARD6), CARD-containing proteins of unique structure. CARD6 associates with microtubules and interacts with receptor-interacting protein (RIP)-like interacting caspase-like apoptosis regulatory protein kinase (RICK), a CARD-containing member of the RIP family of protein kinases. These kinases are involved in multiple NF-κB signaling pathways important for innate and adaptive immune responses. Surprisingly, the CARDs of CARD6 and RICK were not required for their interaction; instead, mutational analysis revealed that the CARD of CARD6 negatively controls the association of these molecules. CARD6 also binds to RIP1, a RIP kinase homologue that lacks a CARD but contains a C-terminal death domain. Coexpression of RICK targets CARD6 to aggresomes via a mechanism that requires the CARD of RICK. Importantly, CARD6 expression has a synergistic effect on NF-κB activation induced by several independent signal transduction pathways. In summary, our results indicate that CARD6 is a regulator of NF-κB activation that modulates the functions of RIP kinase family members.

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